Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

Jia-Yue Xu; Fang-Yuan Liu; Shao-Xuan Liu; Liang-Zhen Xie; Jia Li; Yu-Ting Ma; Feng-Juan Han

doi:10.1155/2021/6852867

Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

Xu, Jia-Yue;Liu, Fang-Yuan;Liu, Shao-Xuan;Xie, Liang-Zhen;Li, Jia;Ma, Yu-Ting;Han, Feng-Juan 2021-12-06 00:00:00 Hindawi Journal of Oncology Volume 2021, Article ID 6852867, 10 pages https://doi.org/10.1155/2021/6852867 Review Article Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects 1 1 1 1,2 2 Jia-Yue Xu , Fang-Yuan Liu , Shao-Xuan Liu , Liang-Zhen Xie , Jia Li , 1 2 Yu-Ting Ma, and Feng-Juan Han Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, Harbin 150040, China Department of Obstetrics and Gynecology, %e First Aﬃliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China Correspondence should be addressed to Feng-Juan Han; hanfengjuan2004@163.com Received 15 August 2021; Revised 3 October 2021; Accepted 22 November 2021; Published 6 December 2021 Academic Editor: Ashok Pandurangan Copyright © 2021 Jia-Yue Xu et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ovarian cancer (OC) is a common malignant tumor of the female reproductive system and has a high morbidity and mortality rate. 0e progression and metastasis of OC are complex and involve multiple signaling pathways. 0e Wnt/β-catenin signaling pathwayiscloselyrelatedtoOC,andthereforeblockingtheactivationoftheWnt/β-cateninsignalingdirectlyorinhibitingrelated genes, and molecular targets is of great value in treating OC. Toxicities such as myelotoxicity, cardiotoxicity, genotoxicity, and vasospasm arethemajorsideeﬀectsfor commonanticancerdrugsand arewelldocumented.0ere is,therefore,a needtodevelop new, eﬀective, safer, and more aﬀordable anticancer drugs from alternative sources. In recent years, plant-derived Chinese medicine monomers have drawn increasing attention due to their high safety, low toxicity, minimal side eﬀects, and antitumor eﬀects.Plant-derivedChinesemedicinemonomersareeﬀectiveagainstmultipletargetsandcanregulatethegrowth,proliferation, apoptosis, invasion, and migration of OC as well as reverse drug resistance by regulating the Wnt/β-catenin signaling pathway. In this review, we summarize and provide mechanisms and prospects for the use of plant-derived Chinese medicines for the prevention and treatment of OC. diagnosis [4]. 0e treatment of OC is based chieﬂy on 1. Introduction surgery, adjuvant postoperative chemotherapy or nonad- Ovarian cancer (OC) is one of the most common gyneco- jacent chemotherapy, molecular-targeted therapy, and other logical malignancies and is a serious threat to women’s lives comprehensive treatments. About 80% of patients can and health. OC is insidious, with no typical symptoms in the achieve complete clinical remission through surgery com- early stage, and most patients present with stage III/IV bined with chemotherapy, but there are still patients who diseaseatthetimeofdiagnosis[1].0erewereabout300,000 cannot accept surgery or the toxic side eﬀects of chemo- new cases of OC worldwide in 2018, accounting for 3.4% of therapy drugs, which leads to limitations in these methods the total number of female malignant tumor cases [2]. [5, 6]. Ovarian cancer mortality has declined since the mid-1970s Toxicities such as myelotoxicity, cardiotoxicity, geno- due to reductions in incidence and improvements in toxicity, pulmonary toxicity, cutaneous toxicity, and vaso- treatment in recent decades [3]. But despite these advances, spasm are the major side eﬀects for common anticancer the survival rate for OC has changed only modestly in recent drugs, such as 5-ﬂuorouracil, doxorubicin, and bleomycin, decades, even in high-resource countries, such as the United and are well documented. 0ere is, therefore, a need to States and Canada, and remains at only 47% ﬁve years after develop new, eﬀective, safer, and more aﬀordable anticancer 2 Journal of Oncology various cancers [21]. Cadherin is a calcium-dependent drugs from alternative sources. Recently, plant-derived Chinese medicines, with a broad target range and low side transmembrane glycoprotein that mediates the connections between epithelial cells [22]. E-cadherins can form dimers, eﬀects, have begun to play a major role in treating tumors. Many plant-derived Chinese medicines used for treating andthesezipper-likestructuresarethebasisofcelladhesion. various tumors have beneﬁcial eﬀects, including inhibiting When the expression of E-cadherin is abnormal or the the occurrence and development of cancer and prolonging concentration of Ca2+ decreases, the dimers separate and the survival time of cancer patients. With the deepening of the cell adhesion will decrease [23]. 0e mature E-cadherin molecular biology research on the pathogenesis of OC, structure includes a C-terminal intracellular domain, a various signaling pathways that regulate OC have attracted transmembrane hydrophobic domain, and an N-terminal widespread attention, such as the Wnt/β-catenin, JAK/ extracellular domain [24]. Its C-terminal intracellular do- STAT, PI3K/AKT, and NF-κB signaling pathways [7, 8]. 0e main forms a complex with multiple proteins, including α-catenin, pl20, actin, and β-catenin [25]. 0erefore, use of plant-derived Chinese medicines to target Wnt/ β-cateninsignalingtotreatOChasbeen activelyexploredby E-cadherin can bind β-catenin, ﬁx it on the cell membrane, and inhibit β-catenin from entering the nucleus, thereby many groups, and the purpose of this review was to sum- marize this research and to provide mechanisms and antagonizing the Wnt signaling pathway, whereas loss of prospects for the use of plant-derived Chinese medicines for cadherin-mediated cell adhesion can promote β-catenin the prevention and treatment of OC. signaling [26, 27]. In vivo, the loss of E-cadherin can release β-catenin from its binding to the cell membrane [28, 29], which means that a reduction in the expression of E-cad- 2. The Wnt/β-Catenin Signaling Pathway herin can enhance nuclear β-catenin signaling events in the As one of the chief signaling pathways in most organisms, presence of Wnt. According to the model of canonical Wnt the Wnt/β-catenin signaling pathway is essential for em- signaling, the accumulation of free cytoplasmic β-catenin and its nuclear import are important steps. Within the bryonic development and for adult tissue homeostasis and regeneration [9, 10]. In 1982, Nusse and Varmus discovered nucleus, β-catenin speciﬁcally binds to proteins of the TCF/ LEF family of transcription factors that activate the tran- the Wnt gene in mouse breast cancer cells, which was also known as the Int1 gene at the time [11]. Later studies found scription of Wnt target genes [30]. 0us, the loss of E-cadherin can increase LEF/TCF-β-catenin signaling, that the Int1 gene and the Drosophila Wingless gene (Wingless)werehomologousgenes,andﬁnallytheInt1gene which might be explained by cadherin and LEF/TCF having and the Wingless gene were collectively referred to as the similar binding modes to β-catenin [31]. Wnt gene [12]. Further studies revealed that Wnt proteins In normal mature cells, the Wnt pathway is turned oﬀ, control a canonical signaling pathway through the key ef- and thedestruction complex,which is composed of axinand fector ß-catenin. 0us, the pathway is also known as the its tumor suppressor partners APC, GSK-3β, and CK1, is Wnt/β-catenin signaling pathway [13]. formed. 0e destruction complex phosphorylates β-catenin and targets it for proteasomal degradation, thus maintaining 0e Wnt signaling pathway includes the Wnt gene family and Wnt receptor. 0ere are a total of 19 Wnt family low levels of cytoplasmic β-catenin. 0e graphical repre- sentation of these functions is shown in Figure 1(a). members (Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, etc.) dis- covered so far, and these play critical roles in regulating However, under pathological or other abnormal states, the proliferation, diﬀerentiation, growth, and so forth [14, 15]. Wnt signaling pathway can be triggered. Wnt proteins are Depending on its mode of action, Wnt signaling is classiﬁed secreted molecules that are acylated by porcupine and then as the canonical Wnt signaling pathway (the Wnt/β-catenin bind to the seven-transmembrane receptor Fzd and lipo- signaling pathway), the Wnt/Ca2+ signaling pathway, or the protein-receptor-related protein (LRP) 5/6, thus activating Wnt/PCP signaling pathway [16]. Among these, canonical the Dsh proteins. Dsh then recruits axin, which inhibits the Wnt/β-catenin signaling is the most important [17] and is formation of the destruction complex, thus allowing the speciﬁc focus of this review. β-catenin to accumulate in the cytoplasm and translocate into thenucleus where it binds to TCF/LEF and activates the 0e main members of Wnt/β-catenin signaling include Wnt protein, ubiquitin protein, β-catenin, frizzled (Fzd), transcription of Wnt target genes like c-Myc, cyclin D1, MMP7, MMP9, and so forth, as shown in Figure 1(b). A casein kinase 1 (CK1), glycogen synthase kinase 3β (GSK- 3β), axin, adenomatous polyposis coli (APC), disheveled considerable number of studies have shown that Wnt/ (Dsh), T-cell factor/lymphocyte enhancer factor (TCF/LEF), β-catenin signaling is involved in controlling many cellular and so on [18]. In the canonical Wnt signaling pathway, processes, including proliferation and diﬀerentiation, and β-catenin is an important protein with transcriptional thus is involved in the pathology of numerous diseases such regulatory activity in the transduction pathway. 0e amount ascardiacandvasculardisease[32]andcancertonamejusta and phosphorylation state of β-catenin in the cell directly few. determineswhetherthecanonicalWntpathway isturnedon or oﬀ [19]. 3. The Wnt/β-Catenin Signaling Pathway in OC As a homophilic adhesive complex to stabilize the cell contact surface, E-cadherin also plays a role in the Wnt A large body of evidence suggests that compared with signaling pathway [20]. Recent evidence indicates that the normal ovarian cells, Wnt pathway component proteins, activity and expression levels of E-cadherin are critical in such as Wnt ligand, Fzd, LRP5/6, and especially nuclear β-catenin Journal of Oncology 3 OFF ON E-cadherin FZD expression LRP 5/6 LRP 5/6 FZD α-catenin P120 β-catenin DSH AXIN β-catenin CK1 β-catenin β-catenin β-catenin β-catenin Target genes TCF/LEF Target genes TCF/LEF transcription (a) (b) Figure 1: 0e Wnt/β-catenin signaling pathway. (a) “Wnt Signaling OFF.” Without Wnt activation, the destruction complex, composed of axin and its tumor suppressor partners APC, GSK-3β, and CK1, is formed. 0e destruction complex phosphorylates β-catenin and targets it for proteasomal degradation, thus maintaining low levels of β-catenin in the cytoplasm. In addition, the E-cadherin structure includes a C-terminal intracellular domain, a transmembrane hydrophobic domain, and an N-terminal extracellular domain. 0e C-terminal in- tracellular domain forms a complex with multiple proteins, including α-catenin, pl20, actin, and β-catenin. E-cadherin can bind β-catenin and ﬁx it on the cell membrane, thus inhibitingβ-catenin from entering the nucleus and antagonizing the Wnt signaling pathway. (b) “Wnt Signaling ON”. Wnt binds to Fzd/LRP5/6 receptors triggering the phosphorylation of Dsh, which is a negative regulator of the destruction complex. Dsh then recruits axin, which inhibits the formation of the destruction complex and allows β-catenin to accumulate in the cytoplasm and translocate into the nucleus where it binds to TCF/LEF and activates the transcription of Wnt target genes. β-catenin protein, are signiﬁcantly upregulated in OC [33]. extracted from patients with metastatic OC was diﬀerent 0e Wnt signaling pathway plays an important role in the from that of the primary tumor cells, showing the same gene embryonic development of ovarian tissue and in the pro- characteristics as epithelial-mesenchymal transition (EMT), liferation, diﬀerentiation, and malignant transformation of thus conﬁrming that the Wnt/β-catenin pathway is one of ovarian cells [34]. 0e occurrence of OC is closely related to the main signaling pathways involved in EMT. At the same β-catenin in the Wnt pathway. time, the E-cadherin/β-catenin protein complex actively participates in the EMT and mesenchymal to epithelial Existing studies have shown that β-catenin has dual functions. On the one hand, it can be used as a signal transitions [41]. EMT is one of the basic mechanisms in- transduction molecule to mediate the transmission of Wnt volved in organ ﬁbrosis and cancer [42], and cell contact is a signal from the cell membrane to the cytoplasm and nucleus key determinant of EMT. 0e loss of E-cadherin promotes [35, 36]. On the other hand, β-catenin also counteracts the release of β-catenin and thus promotes EMT, while the tumor formation, growth, invasion, and metastasis through expression of E-cadherin can reverse the transformed its alternative function as a cytoskeletal component [37]. In phenotype [43–46], and thus the loss of cell-cell adhesion normal somatic cells, β-catenin, with a rod-shaped super- triggers EMTand is related to diseases involving EMT [41]. coiled structure, forms a complex with E-cadherin at the cell Studies have shown that inhibiting the expression of cell adhesion molecules (such as E-cadherin) and mesenchymal membrane, which plays a role in maintaining the adhesion of homotypic cells and prevents cell movement [38]. Based markers (such as vimentin) is a key process in EMT, while the positive EMTstate (decreased E-cadherin expression) is on this, the Wnt/β-catenin pathway contributes to the oc- currence and development of OC by upregulating the ex- a primary feature of OC and metastasis [47, 48]. pression of β-catenin mRNA, whereas downregulating Barghout et al. [49, 50] found that increasing the activity β-catenin reduces the proliferation activity of OC cells and of β-catenin can induce carboplatin resistance in OC A2780 prevents their migration and invasion. cells, while downregulating the expression of β-catenin 0e mechanism through which the Wnt/β-catenin prevents it from entering the nucleus, which eﬀectively pathway may be involved in regulating the occurrence and increases the sensitivity of OC cells to chemotherapeutic development of OC is mainly related to promoting proto- drugs. Decreasing β-catenin activity can also reverse the oncogene or cell regulatory factor gene transcription and resistance of cancer cells to platinum-based chemothera- peutics. 0erefore, downregulation of β-catenin, MMP7, mediating the expression of antiapoptotic genes [39]. Latiﬁ et al. [40] found that the molecular structure of cells survivin, cyclin, c-Myc, and other proteins in the Wnt/ GSK3β GSK3β β-TrCp APC AXIN APC Wnt 4 Journal of Oncology therapy [73, 74]. A rat model made by subcutaneously β-catenin signaling pathway can reverse EMT, inhibit the proliferation of OC cells, induce apoptosis, and reverse the transplanting HO8910PM OC cells showed that 200μmol/L of HYSA for 24 hours inhibited cell growth and promoted eﬀects of transformation therapy drug resistance. However, the underlying mechanisms for how β-catenin controls the apoptosis in HO8910PM cells [53]. At the same time, they development, proliferation, invasion, and metastasis of OC showed that the expression of β-catenin, MMP7, and sur- remain uncertain. vivin were all downregulated and that the expression of the menin protein was upregulated in OC cells and in rat model 4. Plant-Derived Chinese Medicine tumor tissues. It is therefore suggested that HSYA inhibits thegrowthofOCcellsandpromotestheirapoptosisthrough Monomers on OC via Wnt/ menin overexpression and inhibition of β-catenin expres- β-Catenin Signaling sion, thus inhibiting the activation of the Wnt/β-catenin signaling pathway and reducing the downstream expression Plant-derived Chinese medicine monomers play anticancer of the MMP7 and survivin proteins. eﬀects on regulating the Wnt/β-catenin signaling pathway, thereby inhibiting cell invasion, migration, autophagy, ap- optosis, and cell cycle progression and promoting chemo- 4.3. Emodin. Emodin is a natural anthraquinone derivative therapy sensitivity and reversal of drug resistance. 0e roles that occurs in many widely used Chinese medicinal herbs, of plant-derived Chinese medicine monomers on OC via the such as Rheum palmatum, Polygonum cuspidatum, and Wnt/β-catenin signaling are summarized in Table 1. Polygonum multiﬂorum [75]. It has various anticancer, antitumor, and anti-inﬂammatory eﬀects protecting organs 4.1.Resveratrol. Resveratrol is a phenolic substance isolated and tissues, and it is mostly used in basic cancer research or initiallyfromVeratrumgrandiﬂorumandisrichlypresent in incombinationwithotheranticancertherapies[76].Hu[54] grapes, wine, peanuts, soy, and berries and has been found that the proliferation of A2780 and SKOV3 cells attractingtheattentionofresearchersformanydecades[69]. treated with 20μM emodin was not signiﬁcantly inhibited, Resveratrol has certain preventive and therapeutic eﬀects but the invasion ability and EMT were signiﬁcantly weak- against cancer through its antioxidation activity and by ened. 0e epithelial indicators E-cadherin and keratin were regulating metabolism [70, 71], and many studies have signiﬁcantly increased, the expression of the mesenchymal conﬁrmed that resveratrol can inhibit the proliferation, indicators vimentin, N-cadherin, MMP2, and MMP9 was invasion, and migration of OC cells and induce apoptosis. signiﬁcantly decreased, and the expression of p-GSK-3β, Wang and Shi [51] used the MTT method and ﬂow β-catenin, and ZEBI related to the EMT pathway was sig- cytometry to assess the eﬀect of resveratrol on OC A2780 niﬁcantlydecreased,suggestingthatemodininhibitsEMTin cells and found that the expression levels of β-catenin and epithelialOCcellsbyregulatingtheWnt/β-cateninsignaling c-Myc mRNAs and proteins were signiﬁcantly reduced after pathway. treatment with 200μmol/L of resveratrol for 24h. Hou et al. [52]treatedOCSKOV3cellswith20μmol/L,40μmol/L,and 4.4.Oridonin. Oridonin (ORI) is an ent-kaurene tetracyclic 80μmol/L of resveratrol for 24h and found that resveratrol diterpenoid compound isolated from Rabdosia rubescens, could signiﬁcantly inhibit the proliferation, invasion, and and it has various biological and pharmacological activities, migration of OC SKOV3 cells as well as induce their apo- including antitumor, antimicrobial, and anti-inﬂammatory ptosis. At the same time, resveratrol also signiﬁcantly re- eﬀects [77]. In recent years, many in vitro experiments have ducedthemRNAexpressionlevelsofc-Myc,cyclinA,cyclin shown that it has a signiﬁcant inhibitory eﬀect on more than D1, N-cadherin, and vimentin and the protein expression 20 cancer cell lines [78, 79]. Liu and Guo [55] explored the levelofβ-cateninincells,whilethemRNAexpressionofp21, eﬀect of ORI on the migration and invasion of SKOV3 cells E-cadherin, and GSK-3β was signiﬁcantly increased in a and found that ORI could signiﬁcantly inhibit cell viability, concentration-dependent manner. In addition, resveratrol induce apoptosis,and reduce cell migration.0eir study also could eﬀectively inhibit the growth of OC CAOV3 and found that 5μmol/L, 10μmol/L, and 20μmol/L of ORI for OVCAR3 cells and promote their apoptosis at a concen- 24h increased the expression of E-cadherin and decreased tration of 120μM for 48h. 0e expression level of β-catenin the expression of vimentin, β-catenin, c-Myc, and cyclin D1 decreased signiﬁcantly in both cell types, while the ex- in a dose-dependent manner. 0is suggests that ORI might pression of Wnt2 protein was signiﬁcantly decreased in inhibit the Wnt/β-catenin signaling pathway and thereby CAOV3 cells but signiﬁcantly increased in OVCAR3 cells. inhibit the expression of related cytokines. Taken together, these studies demonstrate that resveratrol can inhibit OC through Wnt/β-catenin signaling [71]. 4.5. Schisandrin B. Schisandrin B is extracted from the 4.2. Hydroxysaﬄor Yellow A. Hydroxysaﬄor yellow A Chinese medicine Schisandra, and it has pharmacological (HSYA) is among the major bioactive and water-soluble eﬀects such as promoting tumor cell apoptosis, reducing inﬂammationandtissueedema,improvingmicrocirculation compounds isolated from Carthami ﬂos, the ﬂower of Carthamustinctorius [72]. HSYA has various functions such and antioxidation, and expanding blood vessels [80, 81]. Zeng et al. [56] found that 10μmol/L, 20μmol/L, and as inducing tumor cell apoptosis, interfering with angio- genesis,andreversingdrugresistanceduringtransformation 50μmol/L of schisandrin B for 48h inhibited the Journal of Oncology 5 Table 1: Mechanism of plant-derived Chinese medicine monomers on OC via the Wnt/β-catenin signaling pathway. Plant-derived Chinese Targets Mechanism Refs. medicines c-Myc, cyclin A, cyclin D1, N-cadherin, Inhibiting proliferation, invasion, and migration; Resveratrol vimentin, β-catenin, E-cadherin, p21, [51, 52] inducing apoptosis Wnt3a, GSK-3β Hydroxysaﬄor yellow A β-Catenin, MMP7, survivin, menin Inhibiting proliferation; inducing apoptosis [53] E-cadherin, keratin, vimentin, N- Emodin cadherin, MMP2, MMP9, p-GSK-3β, Inhibiting invasion; reversal of EMT [54] β-catenin, ZEBI Vimentin, c-Myc, cyclin D1, E-cadherin, Inhibiting proliferation, invasion and migration; Oridonin [55] β-catenin inducing apoptosis Schisandrin B β-Catenin, c-Myc, cyclin D1 Inducing apoptosis; blocking cell cycle progression [56] Apigenin β-Catenin, E-cadherin Inhibiting invasion and migration [57, 58] p-AKT, p-GSK-3β, β-catenin, c-Myc, Camellia sinensis Inhibiting proliferation [59, 60] p-β-catenin Icariin β-Catenin, c-Myc, cyclin D1 Inhibiting proliferation [61] Epigallocatechin-3-gallate β-Catenin, cyclin D1 Inducing apoptosis; blocking cell cycle progression [62] Inhibiting proliferation and migration; inducing Paeonol Bcl-2, Bax, β-catenin, c-Myc [63, 64] apoptosis; blocking cell cycle progression p-GSK3β, β-catenin, E-cadherin, Inhibiting proliferation, invasion, and migration; Tetrandrine [65, 66] N-cadherin, vimentin reversal of EMT Inhibiting proliferation; inducing apoptosis; blocking Proanthocyanidins β-Catenin, cyclin D1, c-Myc cell cycle progression; reversing transformation [67] therapy resistance Inhibiting proliferation, invasion, and migration; Naringin β-Catenin, cyclin D1, c-Myc [68] reversing transformation therapy resistance proliferation of SKOV3 cells in both a time- and dose-de- reduced the viability of OCSLCs compared with the control pendent manner. Schisandrin B can also block cell cycle group. TFS inhibited clonal expansion, and tumor sphere progression and reduce the protein expression levels of formation reduced the cells’ self-renewal capacity and was β-catenin, c-Myc, and cyclin D1. 0ese results suggest that showntodownregulatetheexpressionofp-AKT,p-GSK-3β, schisandrin B may reduce the proliferation of SKOV3 cells β-catenin, and c-Myc proteins while upregulating the and block cell cycle progression by inhibiting the Wnt/ phosphorylation of β-catenin thereby inhibiting the Wnt/ β-catenin signaling pathway. β-catenin signaling pathway. It is therefore suggested that TFS can inhibit thegrowth and proliferation of OCSLCsand reduce their stem-like characteristics through inhibition of 4.6. Apigenin. Apigenin is a ﬂavonoid derived from vege- the Wnt/β-catenin signaling pathway. tables, fruits, tea, and beans [82], and it has some eﬀect on preventing and treating cancer, reducing the toxicity of chemotherapy, and reversing drug resistance [83]. Zhang 4.8. Icariin. Icariin is the principal active ingredient in the et al. [57] found that 30μmol/L of apigenin for 24h could Chinese medicine Epimedium. As a new type of ﬂavonoid eﬀectively inhibit the migration and invasiveness of HO8910 anticancer drug, it has demonstrated signiﬁcant antitumor OC cells, and it can also downregulate β-catenin and eﬀects [86]. Chen et al. [61] found that 20μg/ml, 40μg/ml, E-cadherin, which are the downstream eﬀectors of the Wnt and60μg/mloficariinfor24hcouldsigniﬁcantlyinhibitthe signaling pathway. 0e expression level modulation of genes growthandproliferationofCAOV3OCcells,whileRT-PCR and proteins may therefore be achieved by inhibiting the showed that icariin could reduce β-catenin mRNA tran- Wnt/β-catenin signaling pathway. Indeed, cytological scription (thus inhibiting the transcription of the Wnt analysis, western blotting, and immunoﬂuorescent staining signaling pathway target genes c-Myc and cyclin D1) and Western blot conﬁrmed that the compound could down- all suggest that apigenin induces autophagy-mediated downregulation of β-catenin in treated cells, thereby regulate the protein expression of β-catenin, c-Myc, and inhibiting the Wnt/β-catenin signaling pathway [58]. cyclin D1. 0ese results suggest that icariin can inhibit the proliferation of human CAOV3 cells and that this might be achievedbyinhibitingtheWnt/β-cateninsignalingpathway. 4.7. Tea (Camellia sinensis) Flower Saponins. Tea (Camellia sinensis) ﬂower saponins (TFS) has antiallergic and anti- tumor eﬀects [84, 85]. Chen et al. [59, 60] studied the eﬀects 4.9. Epigallocatechin-3-gallate. Epigallocatechin-3-gallate and mechanisms of TFS on the proliferation and diﬀeren- (EGCG) is extracted from green tea and has been shown to have multiple eﬀects on both pathological and physiological tiationofovariancancerstem-likecells(OCSLCs)andfound that doses of 2.5μg/ml, 3.0μg/ml, 3.5μg/ml, and 4.0μg/ml processes in humans [87]. In recent years, a large number of 6 Journal of Oncology against free radical-related diseases [93, 94]. Recent studies studies have conﬁrmed that EGCG has a strong pharma- cological eﬀect on the prevention and treatment of tumors have shown that PCs can inhibit the growth of a variety of tumor cells, promote tumor cell apoptosis, and also an- [88]. Long and Tang [62] studied the eﬀects of EGCG on the proliferation of HO8910 OC cells and Wnt/β-catenin sig- tagonize the toxicity of chemotherapeutics in healthy cells naling pathway-related gene expression in the cells. 0ey achieving good anticancer eﬀects with low toxicity [95]. found that EGCG had a strong antiproliferative eﬀect and Zhangetal.[67]foundthata24htreatmentwith10μg/mlof that 40μg/ml of EGCG the cell cycle of HO8910 cells was PC extracted from the bayberry leaf could inhibit β-catenin, completely blocked. At the same time, EGCG could sig- cyclin D1, and c-Myc protein expression, thereby impeding niﬁcantly reduce the level ofβ-catenin and cyclin D1 mRNA the self-renewal ability of drug-resistant OVCAR3 OC cells, and protein. 0ese results suggest that the mechanism weakening their stem cell characteristics, blocking the cell through which EGCG inhibits the growth of HO8910 OC cycle, and reversing drug resistance. 0e suggested mech- anism for these eﬀects is related to inhibition of the Wnt/ cells may be related to the inhibition of the Wnt/β-catenin signaling pathway. β-catenin signaling pathway. 4.10. Paeonol. Paeonol (PAE) is one of the active compo- 4.13. Naringin. Naringin is a natural ﬂavonoid that mainly nents of Cortex Moutan, which has various anti-inﬂam- exists in the peel and pulp of grapefruit and lime and has matory,antioxidant,andantitumoreﬀects[89].Studieshave exhibited antioxidative, anti-inﬂammatory, and antitumor conﬁrmed that 0.4mmol/L, 0.8mmol/L, and 1.6mmol/L of eﬀects [96, 97]. Naringin can inhibit the proliferation of a PAE for 24h, 48h, and 72h can inhibit the proliferation of variety of tumors, such as cervical cancer [98] and OC [99], A2780 OC cells and promote their apoptosis in a time- and and was shown to inhibit the proliferation of cisplatin re- dose-dependent manner. PAE also has an eﬀect on the sistant OC cells (SKOV3/CDDP) in a dose- and time-de- occurrence and development of OC. Related studies have pendent manner. When combined with cisplatin at 20mol/ found that a certain concentration of PAE can inhibit the L,naringincouldreducetheexpressionofCyclinD1,c-Myc, proliferation of human A2780 OC cells and induce their and β-catenin in SKOV3/CDDP cells and partially reverse apoptosis, block the cells in S phase, and signiﬁcantly reduce cisplatin resistance. 0e mechanism of this activity may be the expression of β-catenin and c-Myc proteins. 0e results related to the Wnt/β-catenin signaling pathway. In addition, of a scratch test showed that the migration ability of the the combination of naringin with cisplatin might prevent A2780 cells decreased signiﬁcantly proportionally to the cell cycle progression, thereby inhibiting the proliferation, drug concentration and exposure time. 0ese results con- invasion, and migration of OC cells [68]. ﬁrmed that PAE inhibits the Wnt/β-catenin signaling pathway by regulating the expression of related proteins, 5. Conclusions and Future Perspectives thereby inhibiting the growth of A2780 cells and inducing apoptosis [63, 64]. 0e Wnt/β-catenin pathway is an important target for treating OC, and many studies have investigated the po- tential therapeutic eﬀects of antibodies and small molecules 4.11.Tetrandrine. Tetrandrine (TET) is a Chinese medicine that target this pathway, with some currently being tested in isolated from the root of Stephania tetrandra S. Moore, [90]. clinical trials [100]. In recent years, accumulating studies Modern pharmacological studies have found that TET acts have concentrated on the eﬀect of plant-derived Chinese as a calcium channel blocker and has immunosuppressive, monomers in treating OC because of their limited side ef- anti-inﬂammatory, antioxidative, and anticancer activities fects and better clinical eﬃcacy. 0e current evidence sug- [91]. Wang et al. [65] found that when A2780 OC cells and gests that plant-derived Chinese monomers can act on ES-2 ovarian clear cancer cells were cultured for 48h, their diﬀerent molecular targets within the Wnt/β-catenin sig- survival rates decreased signiﬁcantly with increasing TET naling pathway to inhibit the metastasis and proliferation of concentration. For the A2780 cells, 5.0μmol/L of TET OC. inhibited the migration and invasion ability and decreased Plant-derived Chinese monomers play a role in the the levels of MiR-21, p-GSK3β, β-catenin, N-cadherin, and development of new targeted therapies for the prevention vimentin, whereas for ES-2 ovarian clear cancer cells, and treatment of OC, but there are still some limitations to 3.0μmol/L TET could do the same. Meanwhile, the these studies. Although some mechanisms of plant-derived E-cadherin protein expression level was signiﬁcantly in- Chinese monomers in antitumor therapy have been dis- creased. Similarly, Jiang and Hou [66] also found that TET cussed, the research on plant-derived Chinese monomers’ couldenhance thesensitivityofSKOV3/PTXcellstoPTXby anticancer eﬀects and their ability to reverse transformation inhibitingtheβ-catenin/c-Myc/cyclinD1signalingpathway. therapy resistance are mostly based on experiments in- volving in vitro cultured cells. Regarding the cytotoxicity of 4.12. Proanthocyanidins. Proanthocyanidins (PCs) are plant-derived Chinese monomers, their bioavailability is not commonly found in plants such as metaplasia, grape seeds, very clear, and further in vitro, in vivo, and clinical studies pine bark, and sorghum bark [92]. PCs are internationally are needed. 0e anticancer eﬀect of plant-derived Chinese recognized natural antioxidants with high bioavailability monomers is multitargeted. At present, the most common and low toxicity, and they have been shown to protect problems in research on the antitumor eﬀects of plant- Journal of Oncology 7 [5] W. Zhang, P. Lei, X. Dong, and X. Men, “Advances in tumor derived Chinese monomers are insuﬃcient validation of markers of ovarian cancer for early diagnosis,” Indian ﬁndings and the scarcity of clinical trials. 0erefore, the Journal of Cancer, vol. 51, no. 7, pp. 72–76, 2014. anticancer eﬀects of these monomers should be further [6] C. Marchetti, L. Muzii, A. Romito, and P. Benedetti Panici, demonstrated at diﬀerent research levels. Carrying out “First-line treatment of women with advanced ovarian clinical trials for plant-derived Chinese monomers with cancer: focus on bevacizumab,” OncoTargets and %erapy, deﬁnite curative eﬀects that are both stable and obvious will vol. 12, pp. 1095–1103, 2019. promotethetranslationofexperimentalresearchresultsinto [7] H. Li, J. Zeng, and K. Shen, “PI3K/AKT/mTOR signaling clinical practice and lay a solid modern medical theory pathway as a therapeutic target for ovarian cancer,” Archives foundation for the clinical application of plant-derived of Gynecology and Obstetrics, vol. 290, no. 6, pp. 1067–1078, Chinese monomers against cancer. 0us, the speciﬁc mechanisms through which plant-derived Chinese mono- [8] W. Hu, T. Liu, C. Ivan et al., “Notch3 pathway alterations in mers inﬂuence the Wnt/β-catenin signaling pathway require ovarian cancer,” Cancer Research, vol. 74, no. 12, deepened studies in the future. pp. 3282–3293, 2014. [9] R. Kleszcz, “Kanoniczna ´sciezka ˙ sygnałowa Wnt,” Postepy Biochemii, vol. 65, no. 3, pp. 183–192, 2019. Data Availability [10] A. Singla, J. Wang, R. Yang, D. S. Geller, D. M. Loeb, and B. H. Hoang, “Wnt signaling in osteosarcoma,” Current No data were used to support this study. Advances in the Science of Osteosarcoma, vol. 1258, pp. 125–139, 2020. Ethical Approval [11] R. Nusse and H. E. Varmus, “Many tumors induced by the mouse mammary tumor virus contain a provirus integrated Not Applicable. in the same region of the host genome,” Cell, vol. 31, no. 1, pp. 99–109, 1982. Consent [12] F. Rijsewijk, M. Schuermann, E. Wagenaar, P. Parren, D. Weigel, and R. Nusse, “0e Drosophila homology of the Not Applicable. mouse mammary oncogene int-1 is identical to the segment polarity gene wingless,” Cell, vol. 50, no. 4, pp. 649–657, Disclosure [13] K. Willert and R. Nusse, “β-catenin: a key mediator of Wnt Jia-Yue Xu and Fang-Yuan Liu should be considered co-ﬁrst signaling,” Current Opinion in Genetics & Development, authors. vol. 8, no. 1, pp. 95–102, 1998. [14] A. Suryawanshi, M. S. Hussein, P. D. Prasad, and Conflicts of Interest S. Manicassamy, “Wnt signaling cascade in dendritic cells and regulation of anti-tumor immunity,” Frontiers in Im- 0e authors declare that they have no competing interests. munology, vol. 11, p. 122, 2020. [15] S. Jati, T. R. Sarraf, D. Naskar, and M. Sen, “Wnt signaling: pathogen incursion and immune defense,” Frontiers in Authors’ Contributions Immunology, vol. 10, p. 2551, 2019. Jia-Yue Xu and Fang-Yuan Liu contributed equally to this [16] T. Zhan, N. Rindtorﬀ, and M. Boutros, “Wnt signaling in work. All authors read and approved the ﬁnal manuscript. cancer,” Oncogene, vol. 36, no. 11, pp. 1461–1473, 2017. [17] B. Li, F. Yu, F. Wu et al., “EZH2 impairs human dental pulp cell mineralization via the Wnt/β-catenin pathway,” Journal Acknowledgments of Dental Research, vol. 97, no. 5, pp. 571–579, 2018. [18] F. H. Tran and J. J. Zheng, “Modulating the Wnt signaling 0is study was supported by the National Natural Science pathwaywithsmallmolecules,”ProteinScience,vol.26,no.4, Foundation of China (82074484). pp. 650–661, 2017. [19] J. Zheng, %e Clinical Intervention of Dingkun Dan on %in References Endometrial Infertility with Kidney-Yang Deﬁciency Syndrome and its Mechanism of Regulating Wnt/β-Catenin Signaling [1] R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, Pathway, Nanjing University of Traditional Chinese Medicine, 2020,” CA: A Cancer Journal for Clinicians, vol. 70, no. 1, Nanjing, China, 2020, https://kns.cnki.net/KCMS/detail/detail. pp. 7–30, 2020. aspx?dbname�CDFDLAST2021&ﬁlename�1020111431. [2] C. J. Cabasag, M. Arnold, J. Butler et al., “0e inﬂuence of [20] M. Takeichi, “Dynamic contacts: rearranging adherens birth cohort and calendar period on global trends in ovarian junctions to drive epithelial remodelling,” Nature Reviews cancer incidence,” International Journal of Cancer, vol. 146, Molecular Cell Biology, vol. 15, no. 6, pp. 397–410, 2014. no. 3, pp. 749–758, 2019. [21] S. H. M. Wong, C. M. Fang, L.-H. Chuah, C. O. Leong, and [3] L. A. Torre, B. Trabert, C. E. DeSantis et al., “Ovarian cancer S. C. Ngai, “E-cadherin: its dysregulation in carcinogenesis statistics, 2018,” CA: A Cancer Journal for Clinicians, vol. 68, and clinical implications,” Critical Reviews in Oncology, no. 4, pp. 284–296, 2018. vol. 121, pp. 11–22, 2018. [4] S. Lheureux, M. Braunstein, and A. M. Oza, “Epithelial ovarian cancer: evolution of management in the era of [22] T. Lecuit and A. S. Yap, “E-cadherin junctions as active mechanical integrators in tissue dynamics,” Nature Cell precision medicine,” CA: A Cancer Journal for Clinicians, vol. 69, no. 4, pp. 280–304, 2019. Biology, vol. 17, no. 5, pp. 533–539, 2015. 8 Journal of Oncology [23] S. S. Pinho, R. Seruca, F. Gartner ¨ et al., “Modulation of [40] A. Latiﬁ, K. Abubaker, N. Castrechini et al., “Cisplatin E-cadherin function and dysfunction by N-glycosylation,” treatment of primary and metastatic epithelial ovarian Cellular and Molecular Life Sciences, vol. 68, no. 6, carcinomas generates residual cells with mesenchymal stem pp. 1011–1020, 2011. cell-like proﬁle,” Journal of Cellular Biochemistry, vol. 112, [24] F. Van Roy and G. Berx, “0e cell-cell adhesion molecule no. 10, pp. 2850–2864, 2011. E-cadherin,” Cellular and Molecular Life Sciences, vol. 65, [41] X. Tian, Z. Liu, B. Niu et al., “E-cadherin/β-catenin complex and the epithelial barrier,” Journal of Biomedicine and no. 23, pp. 3756–3788, 2008. [25] A. M. Mendonsa, T.-Y. Na, and B. M. Gumbiner, “E-cad- Biotechnology, vol. 2011, Article ID 567305, 6 pages, 2011. [42] N. Auersperg, J. Pan, B. D. Grove et al., “E-cadherin induces herin in contact inhibition and cancer,” Oncogene, vol. 37, no. 35, pp. 4769–4780, 2018. mesenchymal-to-epithelial transition in human ovarian [26] F. Fagotto, N. Funayama, U. Gluck, and B. M. Gumbiner, surface epithelium,” Proceedings of the National Academy of “Binding to cadherins antagonizes the signaling activity of Sciences, vol. 96, no. 11, pp. 6249–6254, 1999. beta-catenin during axis formation in Xenopus,” Journal of [43] E. D. Hay and A. Zuk, “Transformations between epithelium Cell Biology, vol. 132, no. 6, pp. 1105–1114, 1996. and mesenchyme: normal, pathological, and experimentally [27] C. J. Gottardi, E. Wong, and B. M. Gumbiner, “E-cadherin induced,” American Journal of Kidney Diseases, vol. 26, no. 4, suppresses cellular transformation by inhibiting β-catenin pp. 678–690, 1995. signaling in an adhesion-independent manner,” Journal of [44] A. Cano, M. A. Perez-Moreno, ´ I. Rodrigo et al., “0e transcription factor snail controls epithelial-mesenchymal Cell Biology, vol. 153, no. 5, pp. 1049–1060, 2001. [28] R. T. Cox, L.-M. Pai, C. Kirkpatrick, J. Stein, and M. Peifer, transitionsbyrepressingE-cadherinexpression,”NatureCell “Roles of the C terminus of armadillo in Wingless signaling Biology, vol. 2, no. 2, pp. 76–83, 2000. in Drosophila,” Genetics, vol. 153, no. 1, pp. 319–332, 1999. [45] K. Vleminckx, L. Vakaet Jr, M. Mareel, W. Fiers, and [29] B. Ciruna and J. Rossant, “FGF signaling regulates mesoderm F. Van Roy, “Genetic manipulation of E-cadherin expression cell fate speciﬁcation and morphogenetic movement at the byepithelial tumor cellsreveals aninvasion suppressorrole,” primitive streak,” Developmental Cell, vol. 1, no. 1, pp. 37–49, Cell, vol. 66, no. 1, pp. 107–119, 1991. 2001. [46] T.Brabletz,A.Jung,S.Reuetal.,“Variable-cateninexpression [30] N. Doumpas, F. Lampart, M. D. Robinson et al., “TCF/LEF in colorectal cancers indicates tumor progression driven by dependent and independent transcriptional regulation of thetumorenvironment,”ProceedingsoftheNationalAcademy Wnt/β-catenin target genes,” %e EMBO Journal, vol. 38, of Sciences, vol. 98, no. 18, pp. 10356–10361, 2001. [47] D. M. Bozhkova and E. G. Poryazova-Markova, “0e epi- no. 2, Article ID e98873, 2019. [31] A. Eger, A. Stockinger, J. Park et al., “β-Catenin and TGFβ thelial-mesenchymal transition, E-cadherin and tumor signalling cooperate to maintain a mesenchymal phenotype progression in ovarian serous tumors,” Folia Medica, vol. 61, after FosER-induced epithelial to mesenchymal transition,” no. 2, pp. 296–302, 2019. Oncogene, vol. 23, no. 15, pp. 2672–2680, 2004. [48] C. Ahluwalia, G. Bhuyan, R. Arora, and P. Sharma, “Epi- [32] S. Foulquier, E. P. Daskalopoulos, G. Lluri, thelial-mesenchymal transition in serous and mucinous K. C. M. Hermans, A. Deb, and W. M. Blankesteijn, “WNT epithelial tumors of the ovary,” Journal of Cancer Research signaling in cardiac and vascular disease,” Pharmacological and %erapeutics, vol. 15, no. 6, pp. 1309–1315, 2019. Reviews, vol. 70, no. 1, pp. 68–141, 2018. [49] S. H. Barghout, N. Zepeda, Z. Xu, H. Steed, C.-H. Lee, and Y. Fu, “Elevated β-catenin activity contributes to carboplatin [33] A. Mostowska, P. Pawlik, S. Sajdak et al., “An analysis of polymorphisms within the Wnt signaling pathway in rela- resistance in A2780cp ovarian cancer cells,” Biochemical and tionto ovarian cancerrisk in a polish population,”Molecular Biophysical Research Communications, vol. 468, no. 1-2, Diagnosis & %erapy, vol. 18, no. 1, pp. 85–91, 2014. pp. 173–178, 2015. [34] T. A. Gatcliﬀe, B. J. Monk, K. Planutis, and R. F. Holcombe, [50] A. B. Nagaraj, P. Joseph, O. Kovalenko et al., “Critical role of “Wnt signaling in ovarian tumorigenesis,” International Wnt/β-catenin signaling in driving epithelial ovarian cancer Journal of Gynecological Cancer, vol. 18, no. 5, pp. 954–962, platinum resistance,” Oncotarget, vol. 6, no. 27, pp. 23720–23734, 2015. [35] E. Krieghoﬀ, J. Behrens, and B. Mayr, “Nucleo-cytoplasmic [51] L. J. Wang and H. R. Shi, “Research on resveratrol inhibiting the growth of ovarian cancer cells and Wnt signaling distribution of β-catenin is regulated by retention,” Journal of Cell Science, vol. 119, no. 7, pp. 1453–1463, 2006. pathway by regulating SIRT1,” Chinese Traditional and [36] L. X. Zhong, Research on the Molecular Mechanism of Herbal Medicine, vol. 50, no. 3, pp. 675–680, 2019. Resveratrol against Ovarian Cancer, Dalian Medical University, [52] Z. Y. Hou, J. Gao, and Y. Wu, “Eﬀects of resveratrol on Dalian, China, 2015, https://kns.cnki.net/KCMS/detail/detail. proliferation activity, proliferation gene mRNA expression aspx?dbname�CDFDLAST2016&ﬁlename�1015625605.nh. and Wnt signaling pathway in ovarian cancer cells,” Chinese [37] C. Song, %e Expression and Clinical Signiﬁcance of EN2 and JournalofOncologicalSurgery, vol.12, no.1,pp. 63–66, 2020. β-catenin in Ovarian Cancer, Qingdao University, Dalian, [53] J.M.Gong,Y.Q.Zhou,andQ.Lin,“HydroxysaﬄoryellowA China, 2020, https://kns.cnki.net/KCMS/detail/detail.aspx? inhibits the growth of ovarian cancer through the Wnt/ β-catenin signaling pathway,” Journal of Medical Research, dbname�CMFD202101&ﬁlename�1020387425.nh. [38] Y. P. Sun, Z. H. Ni, and M. Z. Zhang, “Eﬀect and mechanism vol. 48, no. 10, pp. 131–134, 2019. of hydroxycamptothecin on proliferation and apoptosis of [54] C. Hu, Emodin Inhibits Epithelial-Mesenchymal Transition of lung cancer A549,” Shandong medicine, vol. 60, no. 5, Epithelial Ovarian Cancer Cells and its Mechanism, Shandong pp. 6–9, 2020. University, Jinan, China, 2016, https://kns.cnki.net/KCMS/ [39] B. Yao and Q. H. Zhang, “0e role of Wnt/β-catenin sig- detail/detail.aspx?dbname�CMFD201701&ﬁlename�1016158 naling pathway in the proliferation, migration and invasion 241.nh. of ovarian cancer stem cells,” Chinese Tissue Engineering [55] Y. Liu and J. X. Guo, “Oridonin inhibits the malignant Research, vol. 22, no. 25, pp. 4001–4006, 2018. behavior of human ovarian cancer cells and its mechanism,” Journal of Oncology 9 Modern Preventive Medicine, vol. 48, no. 1, pp. 139–143, [69] J. Breuss, A. Atanasov, and P. Uhrin, “Resveratrol and its 2021. eﬀects on the vascular system,” International Journal of [56] W. Q. Zeng, Q. Xu, and Y. Y. Xu, “Schisandrin B on the Molecular Sciences, vol. 20, no. 7, p. 1523, 2019. proliferation, apoptosis and Wnt/β-catenin signaling path- [70] Y.-Z. Mei, R.-X. Liu, D.-P. Wang, X. Wang, and C.-C. Dai, “Biocatalysis and biotransformation of resveratrol in mi- way of human ovarian cancer Skov3 cell line,” Journal of croorganisms,” Biotechnology Letters, vol. 37, no.1, pp. 9–18, Clinical Oncology, vol. 19, no. 7, pp. 589–593, 2014. [57] J. Z. Zhang, D. L. Ma, and S. H. Zhang, “Apigenin regulates [71] I. Baczko´ and P. E. Light, “Resveratrol and derivatives for the the inﬂuence of Wnt signaling pathway on the invasion of treatment of atrial ﬁbrillation,” Annals of the New York ovarian cancer cells,” Oncology Pharmacy, vol. 7, no. 3, Academy of Sciences, vol. 1348, no. 1, pp. 68–74, 2015. pp. 284–289, 2017. [72] H. Ao, W. Feng, and C. Peng, “Hydroxysaﬄor yellow A: a [58] C.-M. Lin, H.-H. Chen, C.-A. Lin, H.-C. Wu, J. J.-C. Sheu, promising therapeutic agent for a broad spectrum of dis- and H.-J. Chen, “Apigenin-induced lysosomal degradation eases,” Evidence-based Complementary and Alternative of β-catenin in Wnt/β-catenin signaling,” Scientiﬁc Reports, Medicine, vol. 2018, Article ID 8259280, 17 pages, 2018. vol. 7, no. 1, p. 372, 2017. [73] Y. M. Yuan, R. H. Wang, and S. X. Yang, “Research progress [59] L. F. Chen, J. Ren, and Y. Chen, “Eﬀects and mechanism of on the anti-tumor eﬀect of saﬄor yellow,” Chinese Journal of tea tree ﬂower saponins on the proliferation of ovarian Clinical Pharmacology, vol. 33, no. 5, pp. 478–480, 2017. cancer stem cell-like cells,” Journal of Zhejiang University [74] N. Wu, J. Li, H. Luo, D. Wang, and X. Bai, “Hydroxysaﬄor (Agriculture and Life Sciences), vol. 46, no. 6, pp. 667–676, yellow A promotes apoptosis via blocking autophagic ﬂux in liver cancer,” Biomedicine & Pharmacotherapy, vol. 136, [60] L. F. Chen, Inhibition and Mechanism of Tea Tree Flower Article ID 111227, 2021. Saponins on Human Ovarian Cancer Cells and %eir Stem [75] X. Dong, J. Fu, X. Yin et al., “Emodin: a review of its Cells, Zhejiang University, Hangzhou, China, 2020, https:// pharmacology, toxicity and pharmacokinetics,” Phytother- kns.cnki.net/KCMS/detail/detail.aspx?dbname�CMFD20210 apy Research, vol. 30, no. 8, pp. 1207–1218, 2016. 1&ﬁlename�1020314563.nh. [76] S.-Z. Lin, W.-T. Wei, H. Chen et al., “Antitumor activity of [61] R. Chen, Y. Su, and J. Liu, “0e eﬀect of icariin on the emodin against pancreatic cancer depends on its dual role: proliferation of ovarian cancer cells CAOV3 through the promotion of apoptosis and suppression of angiogenesis,” Wnt/β-catenin signaling pathway,” Journal of Medical Re- PLoS One, vol. 7, no. 8, Article ID e42146, 2012. search, vol. 48, no. 3, pp. 44–49, 2019. [77] Y. Zhang, S. Wang, M. Dai, J. Nai, L. Zhu, and H. Sheng, [62] L. Long and L. L. Tang, “Eﬀects of green tea extract epi- “Solubility and bioavailability enhancement of oridonin: a gallocatechin-3-gallate on the proliferation of human review,” Molecules, vol. 25, no. 2, p. 332, 2020. ovarian cancer HO-8910 cells and the expression of Wnt/ [78] D. Li, T. Han, J. Liao et al., “Oridonin, a promising ent- β-catenin signaling pathway related genes,” Chinese Journal kaurane diterpenoid lead compound,” International Journal of Biological Products, vol. 25, no. 09, pp. 1165–1170, 2012. of Molecular Sciences, vol. 17, no. 9, p. 1395, 2016. [63] C. F. Zhang, G. M. Yan, and Macron, “Research progress of [79] Y.Ding,C.Ding,N.Yeetal.,“Discoveryanddevelopmentof paeonol on anticancer eﬀects and mechanisms in the past natural product oridonin-inspired anticancer agents,” Eu- ﬁve years,” Journal of Liaoning University of Traditional ropeanJournalofMedicinalChemistry,vol.122,pp.102–117, Chinese Medicine, vol. 21, no. 10, pp. 158–161, 2019. [64] Q. N. Li, L. L. Wang, and J. M. Tang, “Experimental study of [80] M. I. Nasser, S. Zhu, C. Chen, M. Zhao, H. Huang, and paeonolinhibitingtheproliferationofhumanovariancancer P. Zhu, “A comprehensive review on schisandrin B and its A2780 cells by regulating the Wnt/β-catenin signaling biological properties,” Oxidative Medicine and Cellular pathway,” Chinese Journal of Practical Diagnosis and %er- Longevity, vol. 2020, Article ID 2172740, 13 pages, 2020. apy, vol. 31, no. 11, pp. 1062–1066, 2017. [81] C.-Y. Sun, J. Nie, Z.-L. Zheng et al., “Renoprotective eﬀect of [65] Y. L. Wang, X. G. Jia, and J. Zhu, “Experimental study of scutellarin on cisplatin-induced renal injury in mice: impact tetrandrine regulating the expression of miR-21 to inhibit on inﬂammation, apoptosis, and autophagy,” Biomedicine & epithelial-mesenchymal transition in ovarian cancer,” Pharmacotherapy, vol. 112, Article ID 108647, 2019. Shanghai Journal of Traditional Chinese Medicine, vol. 54, [82] W. L. Li, “Apigenin’s anti-tumor eﬀect and mechanism no. 8, pp. 71–76, 2020. research progress,” China Medical Herald, vol. 11, no. 21, [66] L. Jiang and R. Hou, “Tetrandrine reverses paclitaxel resis- pp. 165–168, 2014. tance in human ovarian cancer via inducing apoptosis, cell [83] L.-P. Chan, T.-H. Chou, H.-Y. Ding et al., “Apigenin induces cycle arrest through β-catenin pathway,” OncoTargets and apoptosis via tumor necrosis factor receptor- and Bcl-2- %erapy, vol. 13, pp. 3631–3639, 2020. mediated pathway and enhances susceptibility of head and [67] Y. Zhang, S. Chen, C. Wei, G. O. Rankin, X. Ye, and neck squamous cell carcinoma to 5-ﬂuorouracil and cis- Y. C. Chen, “Dietary compound proanthocyanidins from platin,” Biochimica et Biophysica Acta (BBA)-General Sub- Chinese bayberry (Myrica rubraSieb. et Zucc.) leaves at- jects, vol. 1820, no. 7, pp. 1081–1091, 2012. tenuate chemotherapy-resistant ovarian cancer stem cell [84] Y. Wang, N. Ren, G. O. Rankin et al., “Anti-proliferative traitsviatargeting the Wnt/β-catenin signaling pathway and eﬀect and cell cycle arrest induced by saponins extracted inducing G1 cell cycle arrest,” Food & Function, vol. 9, no.1, from tea (Camellia sinensis) ﬂower in human ovarian cancer pp. 525–533, 2018. cells,”JournalofFunctionalFoods,vol.37,pp.310–321,2017. [68] H.Zhu,X.Zou, S.Lin,X. Hu,andJ. Gao,“Eﬀectsof naringin [85] H. Matsuda, S. Nakamura, T. Morikawa, O. Muraoka, and on reversing cisplatin resistance and the Wnt/β-catenin M. Yoshikawa, “New biofunctional eﬀects of the ﬂower buds pathway in human ovarian cancer SKOV3/CDDP cells,” of Camellia sinensis and its bioactive acylated oleanane-type Journal of International Medical Research, vol. 48, no. 10, triterpene oligoglycosides,” Journal of Natural Medicines, Article ID 030006051988786, 2020. vol. 70, no. 4, pp. 689–701, 2016. 10 Journal of Oncology [86] T. Wu, S. Wang, J. Wu et al., “Icaritin induces lytic cyto- toxicity in extranodal NK/T-cell lymphoma,” Journal of Experimental&ClinicalCancerResearch, vol. 34, no.1, p.17, [87] C. Chu, J. Deng, Y. Man, and Y. Qu, “Green tea extracts epigallocatechin-3-gallate for diﬀerent treatments,” BioMed Research International, vol. 2017, Article ID 5615647, 9 pages, 2017. [88] S. D. Rao and K. Pagidas, “Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells,” Anticancer Re- search, vol. 30, no. 7, pp. 2519–2523, 2010. [89] S.-S. Li, G.-F. Li, L. Liu et al., “Evaluation of paeonol skin- target delivery from its microsponge formulation: in vitro skin permeation and in vivo microdialysis,”PLoSOne, vol. 8, no. 11, Article ID e79881, 2013. [90] T. Liu, X. Liu, and W. Li, “Tetrandrine, a Chinese plant- derived alkaloid, is a potential candidate for cancer che- motherapy,” Oncotarget, vol. 7, no. 26, pp. 40800–40815, [91] N. Bhagya and K. R. Chandrashekar, “Tetrandrine-a mole- cule of wide bioactivity,” Phytochemistry, vol. 125, pp. 5–13, [92] J. Xu, X. Wang, and L. Lei, “Research progress of proan- thocyanidins in the prevention and control of secretory diarrhea,” Chinese Journal of Animal Husbandry, vol. 57, no. 4, pp. 44–48, 2021. [93] C. Sun, K. Mcintyre, A. Saleem, P. S. Haddad, and J. T. Arnason, “0e relationship between antiglycation ac- tivity and procyanidin and phenolic content in commercial grape seed products,” Canadian Journal of Physiology and Pharmacology, vol. 90, no. 2, pp. 167–174, 2012. [94] K. F. Daughenbaugh, J. Holderness, J. C. Graﬀ et al., “Contribution of transcript stability to a conserved pro- cyanidin-induced cytokine response in cδ T cells,” Genes & Immunity, vol. 12, no. 5, pp. 378–389, 2011. [95] F.Y. Zhang, X. Y. Zhao, and D. L. Zhang, “Research progress on anti-tumor eﬀects and mechanisms of proanthocyani- dins,” Chongqing Medical Journal, vol. 41, no. 27, pp. 2887–2889, 2012. [96] D.Dong,L.Xu,L.Yin,Y.Qi,andJ.Peng,“Naringinprevents carbon tetrachloride-induced acute liver injury in mice,” Journal of Functional Foods, vol. 12, pp. 179–191, 2015. [97] A. Yoshinaga, N. Kajiya, K. Oishi et al., “NEU3 inhibitory eﬀect of naringin suppresses cancer cell growth by attenu- ation of EGFR signaling through GM3 ganglioside accu- mulation,” European Journal of Pharmacology, vol. 782, pp. 21–29, 2016. [98] W. J. Yang, L. Wang, and R. Sun, “Eﬀects of diﬀerent concentrations of naringin on proliferation and COX-2 expression of human cervical cancer HeLa cells in vitro,” ChineseJournalofimmunology, vol. 32,no. 8, pp.1200–1203, [99] Y. Wen, C. Y. Liu, and Q. Q. Xing, “0e eﬀect of naringin on the proliferation, apoptosis and migration of human ovarian cancer cell SKOV3,” Journal of Clinical Oncology, vol. 22, no. 12, pp. 1085–1090, 2017. [100] V.H.L.Nguyen,R.Hough,S.Bernaudo,andC.Peng,“Wnt/ β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis,” Journal of Ovarian Research, vol. 12, no. 1, p. 122, 2019. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Oncology Hindawi Publishing Corporation http://www.deepdyve.com/lp/hindawi-publishing-corporation/plant-derived-chinese-medicine-monomers-on-ovarian-cancer-via-the-wnt-zbZfgjR030

Loading next page...

References

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2021 Jia-Yue Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2021/6852867
Publisher site: See Article on Publisher Site

Abstract

Hindawi Journal of Oncology Volume 2021, Article ID 6852867, 10 pages https://doi.org/10.1155/2021/6852867 Review Article Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects 1 1 1 1,2 2 Jia-Yue Xu , Fang-Yuan Liu , Shao-Xuan Liu , Liang-Zhen Xie , Jia Li , 1 2 Yu-Ting Ma, and Feng-Juan Han Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, Harbin 150040, China Department of Obstetrics and Gynecology, %e First Aﬃliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China Correspondence should be addressed to Feng-Juan Han; hanfengjuan2004@163.com Received 15 August 2021; Revised 3 October 2021; Accepted 22 November 2021; Published 6 December 2021 Academic Editor: Ashok Pandurangan Copyright © 2021 Jia-Yue Xu et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ovarian cancer (OC) is a common malignant tumor of the female reproductive system and has a high morbidity and mortality rate. 0e progression and metastasis of OC are complex and involve multiple signaling pathways. 0e Wnt/β-catenin signaling pathwayiscloselyrelatedtoOC,andthereforeblockingtheactivationoftheWnt/β-cateninsignalingdirectlyorinhibitingrelated genes, and molecular targets is of great value in treating OC. Toxicities such as myelotoxicity, cardiotoxicity, genotoxicity, and vasospasm arethemajorsideeﬀectsfor commonanticancerdrugsand arewelldocumented.0ere is,therefore,a needtodevelop new, eﬀective, safer, and more aﬀordable anticancer drugs from alternative sources. In recent years, plant-derived Chinese medicine monomers have drawn increasing attention due to their high safety, low toxicity, minimal side eﬀects, and antitumor eﬀects.Plant-derivedChinesemedicinemonomersareeﬀectiveagainstmultipletargetsandcanregulatethegrowth,proliferation, apoptosis, invasion, and migration of OC as well as reverse drug resistance by regulating the Wnt/β-catenin signaling pathway. In this review, we summarize and provide mechanisms and prospects for the use of plant-derived Chinese medicines for the prevention and treatment of OC. diagnosis [4]. 0e treatment of OC is based chieﬂy on 1. Introduction surgery, adjuvant postoperative chemotherapy or nonad- Ovarian cancer (OC) is one of the most common gyneco- jacent chemotherapy, molecular-targeted therapy, and other logical malignancies and is a serious threat to women’s lives comprehensive treatments. About 80% of patients can and health. OC is insidious, with no typical symptoms in the achieve complete clinical remission through surgery com- early stage, and most patients present with stage III/IV bined with chemotherapy, but there are still patients who diseaseatthetimeofdiagnosis[1].0erewereabout300,000 cannot accept surgery or the toxic side eﬀects of chemo- new cases of OC worldwide in 2018, accounting for 3.4% of therapy drugs, which leads to limitations in these methods the total number of female malignant tumor cases [2]. [5, 6]. Ovarian cancer mortality has declined since the mid-1970s Toxicities such as myelotoxicity, cardiotoxicity, geno- due to reductions in incidence and improvements in toxicity, pulmonary toxicity, cutaneous toxicity, and vaso- treatment in recent decades [3]. But despite these advances, spasm are the major side eﬀects for common anticancer the survival rate for OC has changed only modestly in recent drugs, such as 5-ﬂuorouracil, doxorubicin, and bleomycin, decades, even in high-resource countries, such as the United and are well documented. 0ere is, therefore, a need to States and Canada, and remains at only 47% ﬁve years after develop new, eﬀective, safer, and more aﬀordable anticancer 2 Journal of Oncology various cancers [21]. Cadherin is a calcium-dependent drugs from alternative sources. Recently, plant-derived Chinese medicines, with a broad target range and low side transmembrane glycoprotein that mediates the connections between epithelial cells [22]. E-cadherins can form dimers, eﬀects, have begun to play a major role in treating tumors. Many plant-derived Chinese medicines used for treating andthesezipper-likestructuresarethebasisofcelladhesion. various tumors have beneﬁcial eﬀects, including inhibiting When the expression of E-cadherin is abnormal or the the occurrence and development of cancer and prolonging concentration of Ca2+ decreases, the dimers separate and the survival time of cancer patients. With the deepening of the cell adhesion will decrease [23]. 0e mature E-cadherin molecular biology research on the pathogenesis of OC, structure includes a C-terminal intracellular domain, a various signaling pathways that regulate OC have attracted transmembrane hydrophobic domain, and an N-terminal widespread attention, such as the Wnt/β-catenin, JAK/ extracellular domain [24]. Its C-terminal intracellular do- STAT, PI3K/AKT, and NF-κB signaling pathways [7, 8]. 0e main forms a complex with multiple proteins, including α-catenin, pl20, actin, and β-catenin [25]. 0erefore, use of plant-derived Chinese medicines to target Wnt/ β-cateninsignalingtotreatOChasbeen activelyexploredby E-cadherin can bind β-catenin, ﬁx it on the cell membrane, and inhibit β-catenin from entering the nucleus, thereby many groups, and the purpose of this review was to sum- marize this research and to provide mechanisms and antagonizing the Wnt signaling pathway, whereas loss of prospects for the use of plant-derived Chinese medicines for cadherin-mediated cell adhesion can promote β-catenin the prevention and treatment of OC. signaling [26, 27]. In vivo, the loss of E-cadherin can release β-catenin from its binding to the cell membrane [28, 29], which means that a reduction in the expression of E-cad- 2. The Wnt/β-Catenin Signaling Pathway herin can enhance nuclear β-catenin signaling events in the As one of the chief signaling pathways in most organisms, presence of Wnt. According to the model of canonical Wnt the Wnt/β-catenin signaling pathway is essential for em- signaling, the accumulation of free cytoplasmic β-catenin and its nuclear import are important steps. Within the bryonic development and for adult tissue homeostasis and regeneration [9, 10]. In 1982, Nusse and Varmus discovered nucleus, β-catenin speciﬁcally binds to proteins of the TCF/ LEF family of transcription factors that activate the tran- the Wnt gene in mouse breast cancer cells, which was also known as the Int1 gene at the time [11]. Later studies found scription of Wnt target genes [30]. 0us, the loss of E-cadherin can increase LEF/TCF-β-catenin signaling, that the Int1 gene and the Drosophila Wingless gene (Wingless)werehomologousgenes,andﬁnallytheInt1gene which might be explained by cadherin and LEF/TCF having and the Wingless gene were collectively referred to as the similar binding modes to β-catenin [31]. Wnt gene [12]. Further studies revealed that Wnt proteins In normal mature cells, the Wnt pathway is turned oﬀ, control a canonical signaling pathway through the key ef- and thedestruction complex,which is composed of axinand fector ß-catenin. 0us, the pathway is also known as the its tumor suppressor partners APC, GSK-3β, and CK1, is Wnt/β-catenin signaling pathway [13]. formed. 0e destruction complex phosphorylates β-catenin and targets it for proteasomal degradation, thus maintaining 0e Wnt signaling pathway includes the Wnt gene family and Wnt receptor. 0ere are a total of 19 Wnt family low levels of cytoplasmic β-catenin. 0e graphical repre- sentation of these functions is shown in Figure 1(a). members (Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, etc.) dis- covered so far, and these play critical roles in regulating However, under pathological or other abnormal states, the proliferation, diﬀerentiation, growth, and so forth [14, 15]. Wnt signaling pathway can be triggered. Wnt proteins are Depending on its mode of action, Wnt signaling is classiﬁed secreted molecules that are acylated by porcupine and then as the canonical Wnt signaling pathway (the Wnt/β-catenin bind to the seven-transmembrane receptor Fzd and lipo- signaling pathway), the Wnt/Ca2+ signaling pathway, or the protein-receptor-related protein (LRP) 5/6, thus activating Wnt/PCP signaling pathway [16]. Among these, canonical the Dsh proteins. Dsh then recruits axin, which inhibits the Wnt/β-catenin signaling is the most important [17] and is formation of the destruction complex, thus allowing the speciﬁc focus of this review. β-catenin to accumulate in the cytoplasm and translocate into thenucleus where it binds to TCF/LEF and activates the 0e main members of Wnt/β-catenin signaling include Wnt protein, ubiquitin protein, β-catenin, frizzled (Fzd), transcription of Wnt target genes like c-Myc, cyclin D1, MMP7, MMP9, and so forth, as shown in Figure 1(b). A casein kinase 1 (CK1), glycogen synthase kinase 3β (GSK- 3β), axin, adenomatous polyposis coli (APC), disheveled considerable number of studies have shown that Wnt/ (Dsh), T-cell factor/lymphocyte enhancer factor (TCF/LEF), β-catenin signaling is involved in controlling many cellular and so on [18]. In the canonical Wnt signaling pathway, processes, including proliferation and diﬀerentiation, and β-catenin is an important protein with transcriptional thus is involved in the pathology of numerous diseases such regulatory activity in the transduction pathway. 0e amount ascardiacandvasculardisease[32]andcancertonamejusta and phosphorylation state of β-catenin in the cell directly few. determineswhetherthecanonicalWntpathway isturnedon or oﬀ [19]. 3. The Wnt/β-Catenin Signaling Pathway in OC As a homophilic adhesive complex to stabilize the cell contact surface, E-cadherin also plays a role in the Wnt A large body of evidence suggests that compared with signaling pathway [20]. Recent evidence indicates that the normal ovarian cells, Wnt pathway component proteins, activity and expression levels of E-cadherin are critical in such as Wnt ligand, Fzd, LRP5/6, and especially nuclear β-catenin Journal of Oncology 3 OFF ON E-cadherin FZD expression LRP 5/6 LRP 5/6 FZD α-catenin P120 β-catenin DSH AXIN β-catenin CK1 β-catenin β-catenin β-catenin β-catenin Target genes TCF/LEF Target genes TCF/LEF transcription (a) (b) Figure 1: 0e Wnt/β-catenin signaling pathway. (a) “Wnt Signaling OFF.” Without Wnt activation, the destruction complex, composed of axin and its tumor suppressor partners APC, GSK-3β, and CK1, is formed. 0e destruction complex phosphorylates β-catenin and targets it for proteasomal degradation, thus maintaining low levels of β-catenin in the cytoplasm. In addition, the E-cadherin structure includes a C-terminal intracellular domain, a transmembrane hydrophobic domain, and an N-terminal extracellular domain. 0e C-terminal in- tracellular domain forms a complex with multiple proteins, including α-catenin, pl20, actin, and β-catenin. E-cadherin can bind β-catenin and ﬁx it on the cell membrane, thus inhibitingβ-catenin from entering the nucleus and antagonizing the Wnt signaling pathway. (b) “Wnt Signaling ON”. Wnt binds to Fzd/LRP5/6 receptors triggering the phosphorylation of Dsh, which is a negative regulator of the destruction complex. Dsh then recruits axin, which inhibits the formation of the destruction complex and allows β-catenin to accumulate in the cytoplasm and translocate into the nucleus where it binds to TCF/LEF and activates the transcription of Wnt target genes. β-catenin protein, are signiﬁcantly upregulated in OC [33]. extracted from patients with metastatic OC was diﬀerent 0e Wnt signaling pathway plays an important role in the from that of the primary tumor cells, showing the same gene embryonic development of ovarian tissue and in the pro- characteristics as epithelial-mesenchymal transition (EMT), liferation, diﬀerentiation, and malignant transformation of thus conﬁrming that the Wnt/β-catenin pathway is one of ovarian cells [34]. 0e occurrence of OC is closely related to the main signaling pathways involved in EMT. At the same β-catenin in the Wnt pathway. time, the E-cadherin/β-catenin protein complex actively participates in the EMT and mesenchymal to epithelial Existing studies have shown that β-catenin has dual functions. On the one hand, it can be used as a signal transitions [41]. EMT is one of the basic mechanisms in- transduction molecule to mediate the transmission of Wnt volved in organ ﬁbrosis and cancer [42], and cell contact is a signal from the cell membrane to the cytoplasm and nucleus key determinant of EMT. 0e loss of E-cadherin promotes [35, 36]. On the other hand, β-catenin also counteracts the release of β-catenin and thus promotes EMT, while the tumor formation, growth, invasion, and metastasis through expression of E-cadherin can reverse the transformed its alternative function as a cytoskeletal component [37]. In phenotype [43–46], and thus the loss of cell-cell adhesion normal somatic cells, β-catenin, with a rod-shaped super- triggers EMTand is related to diseases involving EMT [41]. coiled structure, forms a complex with E-cadherin at the cell Studies have shown that inhibiting the expression of cell adhesion molecules (such as E-cadherin) and mesenchymal membrane, which plays a role in maintaining the adhesion of homotypic cells and prevents cell movement [38]. Based markers (such as vimentin) is a key process in EMT, while the positive EMTstate (decreased E-cadherin expression) is on this, the Wnt/β-catenin pathway contributes to the oc- currence and development of OC by upregulating the ex- a primary feature of OC and metastasis [47, 48]. pression of β-catenin mRNA, whereas downregulating Barghout et al. [49, 50] found that increasing the activity β-catenin reduces the proliferation activity of OC cells and of β-catenin can induce carboplatin resistance in OC A2780 prevents their migration and invasion. cells, while downregulating the expression of β-catenin 0e mechanism through which the Wnt/β-catenin prevents it from entering the nucleus, which eﬀectively pathway may be involved in regulating the occurrence and increases the sensitivity of OC cells to chemotherapeutic development of OC is mainly related to promoting proto- drugs. Decreasing β-catenin activity can also reverse the oncogene or cell regulatory factor gene transcription and resistance of cancer cells to platinum-based chemothera- peutics. 0erefore, downregulation of β-catenin, MMP7, mediating the expression of antiapoptotic genes [39]. Latiﬁ et al. [40] found that the molecular structure of cells survivin, cyclin, c-Myc, and other proteins in the Wnt/ GSK3β GSK3β β-TrCp APC AXIN APC Wnt 4 Journal of Oncology therapy [73, 74]. A rat model made by subcutaneously β-catenin signaling pathway can reverse EMT, inhibit the proliferation of OC cells, induce apoptosis, and reverse the transplanting HO8910PM OC cells showed that 200μmol/L of HYSA for 24 hours inhibited cell growth and promoted eﬀects of transformation therapy drug resistance. However, the underlying mechanisms for how β-catenin controls the apoptosis in HO8910PM cells [53]. At the same time, they development, proliferation, invasion, and metastasis of OC showed that the expression of β-catenin, MMP7, and sur- remain uncertain. vivin were all downregulated and that the expression of the menin protein was upregulated in OC cells and in rat model 4. Plant-Derived Chinese Medicine tumor tissues. It is therefore suggested that HSYA inhibits thegrowthofOCcellsandpromotestheirapoptosisthrough Monomers on OC via Wnt/ menin overexpression and inhibition of β-catenin expres- β-Catenin Signaling sion, thus inhibiting the activation of the Wnt/β-catenin signaling pathway and reducing the downstream expression Plant-derived Chinese medicine monomers play anticancer of the MMP7 and survivin proteins. eﬀects on regulating the Wnt/β-catenin signaling pathway, thereby inhibiting cell invasion, migration, autophagy, ap- optosis, and cell cycle progression and promoting chemo- 4.3. Emodin. Emodin is a natural anthraquinone derivative therapy sensitivity and reversal of drug resistance. 0e roles that occurs in many widely used Chinese medicinal herbs, of plant-derived Chinese medicine monomers on OC via the such as Rheum palmatum, Polygonum cuspidatum, and Wnt/β-catenin signaling are summarized in Table 1. Polygonum multiﬂorum [75]. It has various anticancer, antitumor, and anti-inﬂammatory eﬀects protecting organs 4.1.Resveratrol. Resveratrol is a phenolic substance isolated and tissues, and it is mostly used in basic cancer research or initiallyfromVeratrumgrandiﬂorumandisrichlypresent in incombinationwithotheranticancertherapies[76].Hu[54] grapes, wine, peanuts, soy, and berries and has been found that the proliferation of A2780 and SKOV3 cells attractingtheattentionofresearchersformanydecades[69]. treated with 20μM emodin was not signiﬁcantly inhibited, Resveratrol has certain preventive and therapeutic eﬀects but the invasion ability and EMT were signiﬁcantly weak- against cancer through its antioxidation activity and by ened. 0e epithelial indicators E-cadherin and keratin were regulating metabolism [70, 71], and many studies have signiﬁcantly increased, the expression of the mesenchymal conﬁrmed that resveratrol can inhibit the proliferation, indicators vimentin, N-cadherin, MMP2, and MMP9 was invasion, and migration of OC cells and induce apoptosis. signiﬁcantly decreased, and the expression of p-GSK-3β, Wang and Shi [51] used the MTT method and ﬂow β-catenin, and ZEBI related to the EMT pathway was sig- cytometry to assess the eﬀect of resveratrol on OC A2780 niﬁcantlydecreased,suggestingthatemodininhibitsEMTin cells and found that the expression levels of β-catenin and epithelialOCcellsbyregulatingtheWnt/β-cateninsignaling c-Myc mRNAs and proteins were signiﬁcantly reduced after pathway. treatment with 200μmol/L of resveratrol for 24h. Hou et al. [52]treatedOCSKOV3cellswith20μmol/L,40μmol/L,and 4.4.Oridonin. Oridonin (ORI) is an ent-kaurene tetracyclic 80μmol/L of resveratrol for 24h and found that resveratrol diterpenoid compound isolated from Rabdosia rubescens, could signiﬁcantly inhibit the proliferation, invasion, and and it has various biological and pharmacological activities, migration of OC SKOV3 cells as well as induce their apo- including antitumor, antimicrobial, and anti-inﬂammatory ptosis. At the same time, resveratrol also signiﬁcantly re- eﬀects [77]. In recent years, many in vitro experiments have ducedthemRNAexpressionlevelsofc-Myc,cyclinA,cyclin shown that it has a signiﬁcant inhibitory eﬀect on more than D1, N-cadherin, and vimentin and the protein expression 20 cancer cell lines [78, 79]. Liu and Guo [55] explored the levelofβ-cateninincells,whilethemRNAexpressionofp21, eﬀect of ORI on the migration and invasion of SKOV3 cells E-cadherin, and GSK-3β was signiﬁcantly increased in a and found that ORI could signiﬁcantly inhibit cell viability, concentration-dependent manner. In addition, resveratrol induce apoptosis,and reduce cell migration.0eir study also could eﬀectively inhibit the growth of OC CAOV3 and found that 5μmol/L, 10μmol/L, and 20μmol/L of ORI for OVCAR3 cells and promote their apoptosis at a concen- 24h increased the expression of E-cadherin and decreased tration of 120μM for 48h. 0e expression level of β-catenin the expression of vimentin, β-catenin, c-Myc, and cyclin D1 decreased signiﬁcantly in both cell types, while the ex- in a dose-dependent manner. 0is suggests that ORI might pression of Wnt2 protein was signiﬁcantly decreased in inhibit the Wnt/β-catenin signaling pathway and thereby CAOV3 cells but signiﬁcantly increased in OVCAR3 cells. inhibit the expression of related cytokines. Taken together, these studies demonstrate that resveratrol can inhibit OC through Wnt/β-catenin signaling [71]. 4.5. Schisandrin B. Schisandrin B is extracted from the 4.2. Hydroxysaﬄor Yellow A. Hydroxysaﬄor yellow A Chinese medicine Schisandra, and it has pharmacological (HSYA) is among the major bioactive and water-soluble eﬀects such as promoting tumor cell apoptosis, reducing inﬂammationandtissueedema,improvingmicrocirculation compounds isolated from Carthami ﬂos, the ﬂower of Carthamustinctorius [72]. HSYA has various functions such and antioxidation, and expanding blood vessels [80, 81]. Zeng et al. [56] found that 10μmol/L, 20μmol/L, and as inducing tumor cell apoptosis, interfering with angio- genesis,andreversingdrugresistanceduringtransformation 50μmol/L of schisandrin B for 48h inhibited the Journal of Oncology 5 Table 1: Mechanism of plant-derived Chinese medicine monomers on OC via the Wnt/β-catenin signaling pathway. Plant-derived Chinese Targets Mechanism Refs. medicines c-Myc, cyclin A, cyclin D1, N-cadherin, Inhibiting proliferation, invasion, and migration; Resveratrol vimentin, β-catenin, E-cadherin, p21, [51, 52] inducing apoptosis Wnt3a, GSK-3β Hydroxysaﬄor yellow A β-Catenin, MMP7, survivin, menin Inhibiting proliferation; inducing apoptosis [53] E-cadherin, keratin, vimentin, N- Emodin cadherin, MMP2, MMP9, p-GSK-3β, Inhibiting invasion; reversal of EMT [54] β-catenin, ZEBI Vimentin, c-Myc, cyclin D1, E-cadherin, Inhibiting proliferation, invasion and migration; Oridonin [55] β-catenin inducing apoptosis Schisandrin B β-Catenin, c-Myc, cyclin D1 Inducing apoptosis; blocking cell cycle progression [56] Apigenin β-Catenin, E-cadherin Inhibiting invasion and migration [57, 58] p-AKT, p-GSK-3β, β-catenin, c-Myc, Camellia sinensis Inhibiting proliferation [59, 60] p-β-catenin Icariin β-Catenin, c-Myc, cyclin D1 Inhibiting proliferation [61] Epigallocatechin-3-gallate β-Catenin, cyclin D1 Inducing apoptosis; blocking cell cycle progression [62] Inhibiting proliferation and migration; inducing Paeonol Bcl-2, Bax, β-catenin, c-Myc [63, 64] apoptosis; blocking cell cycle progression p-GSK3β, β-catenin, E-cadherin, Inhibiting proliferation, invasion, and migration; Tetrandrine [65, 66] N-cadherin, vimentin reversal of EMT Inhibiting proliferation; inducing apoptosis; blocking Proanthocyanidins β-Catenin, cyclin D1, c-Myc cell cycle progression; reversing transformation [67] therapy resistance Inhibiting proliferation, invasion, and migration; Naringin β-Catenin, cyclin D1, c-Myc [68] reversing transformation therapy resistance proliferation of SKOV3 cells in both a time- and dose-de- reduced the viability of OCSLCs compared with the control pendent manner. Schisandrin B can also block cell cycle group. TFS inhibited clonal expansion, and tumor sphere progression and reduce the protein expression levels of formation reduced the cells’ self-renewal capacity and was β-catenin, c-Myc, and cyclin D1. 0ese results suggest that showntodownregulatetheexpressionofp-AKT,p-GSK-3β, schisandrin B may reduce the proliferation of SKOV3 cells β-catenin, and c-Myc proteins while upregulating the and block cell cycle progression by inhibiting the Wnt/ phosphorylation of β-catenin thereby inhibiting the Wnt/ β-catenin signaling pathway. β-catenin signaling pathway. It is therefore suggested that TFS can inhibit thegrowth and proliferation of OCSLCsand reduce their stem-like characteristics through inhibition of 4.6. Apigenin. Apigenin is a ﬂavonoid derived from vege- the Wnt/β-catenin signaling pathway. tables, fruits, tea, and beans [82], and it has some eﬀect on preventing and treating cancer, reducing the toxicity of chemotherapy, and reversing drug resistance [83]. Zhang 4.8. Icariin. Icariin is the principal active ingredient in the et al. [57] found that 30μmol/L of apigenin for 24h could Chinese medicine Epimedium. As a new type of ﬂavonoid eﬀectively inhibit the migration and invasiveness of HO8910 anticancer drug, it has demonstrated signiﬁcant antitumor OC cells, and it can also downregulate β-catenin and eﬀects [86]. Chen et al. [61] found that 20μg/ml, 40μg/ml, E-cadherin, which are the downstream eﬀectors of the Wnt and60μg/mloficariinfor24hcouldsigniﬁcantlyinhibitthe signaling pathway. 0e expression level modulation of genes growthandproliferationofCAOV3OCcells,whileRT-PCR and proteins may therefore be achieved by inhibiting the showed that icariin could reduce β-catenin mRNA tran- Wnt/β-catenin signaling pathway. Indeed, cytological scription (thus inhibiting the transcription of the Wnt analysis, western blotting, and immunoﬂuorescent staining signaling pathway target genes c-Myc and cyclin D1) and Western blot conﬁrmed that the compound could down- all suggest that apigenin induces autophagy-mediated downregulation of β-catenin in treated cells, thereby regulate the protein expression of β-catenin, c-Myc, and inhibiting the Wnt/β-catenin signaling pathway [58]. cyclin D1. 0ese results suggest that icariin can inhibit the proliferation of human CAOV3 cells and that this might be achievedbyinhibitingtheWnt/β-cateninsignalingpathway. 4.7. Tea (Camellia sinensis) Flower Saponins. Tea (Camellia sinensis) ﬂower saponins (TFS) has antiallergic and anti- tumor eﬀects [84, 85]. Chen et al. [59, 60] studied the eﬀects 4.9. Epigallocatechin-3-gallate. Epigallocatechin-3-gallate and mechanisms of TFS on the proliferation and diﬀeren- (EGCG) is extracted from green tea and has been shown to have multiple eﬀects on both pathological and physiological tiationofovariancancerstem-likecells(OCSLCs)andfound that doses of 2.5μg/ml, 3.0μg/ml, 3.5μg/ml, and 4.0μg/ml processes in humans [87]. In recent years, a large number of 6 Journal of Oncology against free radical-related diseases [93, 94]. Recent studies studies have conﬁrmed that EGCG has a strong pharma- cological eﬀect on the prevention and treatment of tumors have shown that PCs can inhibit the growth of a variety of tumor cells, promote tumor cell apoptosis, and also an- [88]. Long and Tang [62] studied the eﬀects of EGCG on the proliferation of HO8910 OC cells and Wnt/β-catenin sig- tagonize the toxicity of chemotherapeutics in healthy cells naling pathway-related gene expression in the cells. 0ey achieving good anticancer eﬀects with low toxicity [95]. found that EGCG had a strong antiproliferative eﬀect and Zhangetal.[67]foundthata24htreatmentwith10μg/mlof that 40μg/ml of EGCG the cell cycle of HO8910 cells was PC extracted from the bayberry leaf could inhibit β-catenin, completely blocked. At the same time, EGCG could sig- cyclin D1, and c-Myc protein expression, thereby impeding niﬁcantly reduce the level ofβ-catenin and cyclin D1 mRNA the self-renewal ability of drug-resistant OVCAR3 OC cells, and protein. 0ese results suggest that the mechanism weakening their stem cell characteristics, blocking the cell through which EGCG inhibits the growth of HO8910 OC cycle, and reversing drug resistance. 0e suggested mech- anism for these eﬀects is related to inhibition of the Wnt/ cells may be related to the inhibition of the Wnt/β-catenin signaling pathway. β-catenin signaling pathway. 4.10. Paeonol. Paeonol (PAE) is one of the active compo- 4.13. Naringin. Naringin is a natural ﬂavonoid that mainly nents of Cortex Moutan, which has various anti-inﬂam- exists in the peel and pulp of grapefruit and lime and has matory,antioxidant,andantitumoreﬀects[89].Studieshave exhibited antioxidative, anti-inﬂammatory, and antitumor conﬁrmed that 0.4mmol/L, 0.8mmol/L, and 1.6mmol/L of eﬀects [96, 97]. Naringin can inhibit the proliferation of a PAE for 24h, 48h, and 72h can inhibit the proliferation of variety of tumors, such as cervical cancer [98] and OC [99], A2780 OC cells and promote their apoptosis in a time- and and was shown to inhibit the proliferation of cisplatin re- dose-dependent manner. PAE also has an eﬀect on the sistant OC cells (SKOV3/CDDP) in a dose- and time-de- occurrence and development of OC. Related studies have pendent manner. When combined with cisplatin at 20mol/ found that a certain concentration of PAE can inhibit the L,naringincouldreducetheexpressionofCyclinD1,c-Myc, proliferation of human A2780 OC cells and induce their and β-catenin in SKOV3/CDDP cells and partially reverse apoptosis, block the cells in S phase, and signiﬁcantly reduce cisplatin resistance. 0e mechanism of this activity may be the expression of β-catenin and c-Myc proteins. 0e results related to the Wnt/β-catenin signaling pathway. In addition, of a scratch test showed that the migration ability of the the combination of naringin with cisplatin might prevent A2780 cells decreased signiﬁcantly proportionally to the cell cycle progression, thereby inhibiting the proliferation, drug concentration and exposure time. 0ese results con- invasion, and migration of OC cells [68]. ﬁrmed that PAE inhibits the Wnt/β-catenin signaling pathway by regulating the expression of related proteins, 5. Conclusions and Future Perspectives thereby inhibiting the growth of A2780 cells and inducing apoptosis [63, 64]. 0e Wnt/β-catenin pathway is an important target for treating OC, and many studies have investigated the po- tential therapeutic eﬀects of antibodies and small molecules 4.11.Tetrandrine. Tetrandrine (TET) is a Chinese medicine that target this pathway, with some currently being tested in isolated from the root of Stephania tetrandra S. Moore, [90]. clinical trials [100]. In recent years, accumulating studies Modern pharmacological studies have found that TET acts have concentrated on the eﬀect of plant-derived Chinese as a calcium channel blocker and has immunosuppressive, monomers in treating OC because of their limited side ef- anti-inﬂammatory, antioxidative, and anticancer activities fects and better clinical eﬃcacy. 0e current evidence sug- [91]. Wang et al. [65] found that when A2780 OC cells and gests that plant-derived Chinese monomers can act on ES-2 ovarian clear cancer cells were cultured for 48h, their diﬀerent molecular targets within the Wnt/β-catenin sig- survival rates decreased signiﬁcantly with increasing TET naling pathway to inhibit the metastasis and proliferation of concentration. For the A2780 cells, 5.0μmol/L of TET OC. inhibited the migration and invasion ability and decreased Plant-derived Chinese monomers play a role in the the levels of MiR-21, p-GSK3β, β-catenin, N-cadherin, and development of new targeted therapies for the prevention vimentin, whereas for ES-2 ovarian clear cancer cells, and treatment of OC, but there are still some limitations to 3.0μmol/L TET could do the same. Meanwhile, the these studies. Although some mechanisms of plant-derived E-cadherin protein expression level was signiﬁcantly in- Chinese monomers in antitumor therapy have been dis- creased. Similarly, Jiang and Hou [66] also found that TET cussed, the research on plant-derived Chinese monomers’ couldenhance thesensitivityofSKOV3/PTXcellstoPTXby anticancer eﬀects and their ability to reverse transformation inhibitingtheβ-catenin/c-Myc/cyclinD1signalingpathway. therapy resistance are mostly based on experiments in- volving in vitro cultured cells. Regarding the cytotoxicity of 4.12. Proanthocyanidins. Proanthocyanidins (PCs) are plant-derived Chinese monomers, their bioavailability is not commonly found in plants such as metaplasia, grape seeds, very clear, and further in vitro, in vivo, and clinical studies pine bark, and sorghum bark [92]. PCs are internationally are needed. 0e anticancer eﬀect of plant-derived Chinese recognized natural antioxidants with high bioavailability monomers is multitargeted. At present, the most common and low toxicity, and they have been shown to protect problems in research on the antitumor eﬀects of plant- Journal of Oncology 7 [5] W. Zhang, P. Lei, X. Dong, and X. Men, “Advances in tumor derived Chinese monomers are insuﬃcient validation of markers of ovarian cancer for early diagnosis,” Indian ﬁndings and the scarcity of clinical trials. 0erefore, the Journal of Cancer, vol. 51, no. 7, pp. 72–76, 2014. anticancer eﬀects of these monomers should be further [6] C. Marchetti, L. Muzii, A. Romito, and P. Benedetti Panici, demonstrated at diﬀerent research levels. Carrying out “First-line treatment of women with advanced ovarian clinical trials for plant-derived Chinese monomers with cancer: focus on bevacizumab,” OncoTargets and %erapy, deﬁnite curative eﬀects that are both stable and obvious will vol. 12, pp. 1095–1103, 2019. promotethetranslationofexperimentalresearchresultsinto [7] H. Li, J. Zeng, and K. Shen, “PI3K/AKT/mTOR signaling clinical practice and lay a solid modern medical theory pathway as a therapeutic target for ovarian cancer,” Archives foundation for the clinical application of plant-derived of Gynecology and Obstetrics, vol. 290, no. 6, pp. 1067–1078, Chinese monomers against cancer. 0us, the speciﬁc mechanisms through which plant-derived Chinese mono- [8] W. Hu, T. Liu, C. Ivan et al., “Notch3 pathway alterations in mers inﬂuence the Wnt/β-catenin signaling pathway require ovarian cancer,” Cancer Research, vol. 74, no. 12, deepened studies in the future. pp. 3282–3293, 2014. [9] R. Kleszcz, “Kanoniczna ´sciezka ˙ sygnałowa Wnt,” Postepy Biochemii, vol. 65, no. 3, pp. 183–192, 2019. Data Availability [10] A. Singla, J. Wang, R. Yang, D. S. Geller, D. M. Loeb, and B. H. Hoang, “Wnt signaling in osteosarcoma,” Current No data were used to support this study. Advances in the Science of Osteosarcoma, vol. 1258, pp. 125–139, 2020. Ethical Approval [11] R. Nusse and H. E. Varmus, “Many tumors induced by the mouse mammary tumor virus contain a provirus integrated Not Applicable. in the same region of the host genome,” Cell, vol. 31, no. 1, pp. 99–109, 1982. Consent [12] F. Rijsewijk, M. Schuermann, E. Wagenaar, P. Parren, D. Weigel, and R. Nusse, “0e Drosophila homology of the Not Applicable. mouse mammary oncogene int-1 is identical to the segment polarity gene wingless,” Cell, vol. 50, no. 4, pp. 649–657, Disclosure [13] K. Willert and R. Nusse, “β-catenin: a key mediator of Wnt Jia-Yue Xu and Fang-Yuan Liu should be considered co-ﬁrst signaling,” Current Opinion in Genetics & Development, authors. vol. 8, no. 1, pp. 95–102, 1998. [14] A. Suryawanshi, M. S. Hussein, P. D. Prasad, and Conflicts of Interest S. Manicassamy, “Wnt signaling cascade in dendritic cells and regulation of anti-tumor immunity,” Frontiers in Im- 0e authors declare that they have no competing interests. munology, vol. 11, p. 122, 2020. [15] S. Jati, T. R. Sarraf, D. Naskar, and M. Sen, “Wnt signaling: pathogen incursion and immune defense,” Frontiers in Authors’ Contributions Immunology, vol. 10, p. 2551, 2019. Jia-Yue Xu and Fang-Yuan Liu contributed equally to this [16] T. Zhan, N. Rindtorﬀ, and M. Boutros, “Wnt signaling in work. All authors read and approved the ﬁnal manuscript. cancer,” Oncogene, vol. 36, no. 11, pp. 1461–1473, 2017. [17] B. Li, F. Yu, F. Wu et al., “EZH2 impairs human dental pulp cell mineralization via the Wnt/β-catenin pathway,” Journal Acknowledgments of Dental Research, vol. 97, no. 5, pp. 571–579, 2018. [18] F. H. Tran and J. J. Zheng, “Modulating the Wnt signaling 0is study was supported by the National Natural Science pathwaywithsmallmolecules,”ProteinScience,vol.26,no.4, Foundation of China (82074484). pp. 650–661, 2017. [19] J. Zheng, %e Clinical Intervention of Dingkun Dan on %in References Endometrial Infertility with Kidney-Yang Deﬁciency Syndrome and its Mechanism of Regulating Wnt/β-Catenin Signaling [1] R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, Pathway, Nanjing University of Traditional Chinese Medicine, 2020,” CA: A Cancer Journal for Clinicians, vol. 70, no. 1, Nanjing, China, 2020, https://kns.cnki.net/KCMS/detail/detail. pp. 7–30, 2020. aspx?dbname�CDFDLAST2021&ﬁlename�1020111431. [2] C. J. Cabasag, M. Arnold, J. Butler et al., “0e inﬂuence of [20] M. Takeichi, “Dynamic contacts: rearranging adherens birth cohort and calendar period on global trends in ovarian junctions to drive epithelial remodelling,” Nature Reviews cancer incidence,” International Journal of Cancer, vol. 146, Molecular Cell Biology, vol. 15, no. 6, pp. 397–410, 2014. no. 3, pp. 749–758, 2019. [21] S. H. M. Wong, C. M. Fang, L.-H. Chuah, C. O. Leong, and [3] L. A. Torre, B. Trabert, C. E. DeSantis et al., “Ovarian cancer S. C. Ngai, “E-cadherin: its dysregulation in carcinogenesis statistics, 2018,” CA: A Cancer Journal for Clinicians, vol. 68, and clinical implications,” Critical Reviews in Oncology, no. 4, pp. 284–296, 2018. vol. 121, pp. 11–22, 2018. [4] S. Lheureux, M. Braunstein, and A. M. Oza, “Epithelial ovarian cancer: evolution of management in the era of [22] T. Lecuit and A. S. Yap, “E-cadherin junctions as active mechanical integrators in tissue dynamics,” Nature Cell precision medicine,” CA: A Cancer Journal for Clinicians, vol. 69, no. 4, pp. 280–304, 2019. Biology, vol. 17, no. 5, pp. 533–539, 2015. 8 Journal of Oncology [23] S. S. Pinho, R. Seruca, F. Gartner ¨ et al., “Modulation of [40] A. Latiﬁ, K. Abubaker, N. Castrechini et al., “Cisplatin E-cadherin function and dysfunction by N-glycosylation,” treatment of primary and metastatic epithelial ovarian Cellular and Molecular Life Sciences, vol. 68, no. 6, carcinomas generates residual cells with mesenchymal stem pp. 1011–1020, 2011. cell-like proﬁle,” Journal of Cellular Biochemistry, vol. 112, [24] F. Van Roy and G. Berx, “0e cell-cell adhesion molecule no. 10, pp. 2850–2864, 2011. E-cadherin,” Cellular and Molecular Life Sciences, vol. 65, [41] X. Tian, Z. Liu, B. Niu et al., “E-cadherin/β-catenin complex and the epithelial barrier,” Journal of Biomedicine and no. 23, pp. 3756–3788, 2008. [25] A. M. Mendonsa, T.-Y. Na, and B. M. Gumbiner, “E-cad- Biotechnology, vol. 2011, Article ID 567305, 6 pages, 2011. [42] N. Auersperg, J. Pan, B. D. Grove et al., “E-cadherin induces herin in contact inhibition and cancer,” Oncogene, vol. 37, no. 35, pp. 4769–4780, 2018. mesenchymal-to-epithelial transition in human ovarian [26] F. Fagotto, N. Funayama, U. Gluck, and B. M. Gumbiner, surface epithelium,” Proceedings of the National Academy of “Binding to cadherins antagonizes the signaling activity of Sciences, vol. 96, no. 11, pp. 6249–6254, 1999. beta-catenin during axis formation in Xenopus,” Journal of [43] E. D. Hay and A. Zuk, “Transformations between epithelium Cell Biology, vol. 132, no. 6, pp. 1105–1114, 1996. and mesenchyme: normal, pathological, and experimentally [27] C. J. Gottardi, E. Wong, and B. M. Gumbiner, “E-cadherin induced,” American Journal of Kidney Diseases, vol. 26, no. 4, suppresses cellular transformation by inhibiting β-catenin pp. 678–690, 1995. signaling in an adhesion-independent manner,” Journal of [44] A. Cano, M. A. Perez-Moreno, ´ I. Rodrigo et al., “0e transcription factor snail controls epithelial-mesenchymal Cell Biology, vol. 153, no. 5, pp. 1049–1060, 2001. [28] R. T. Cox, L.-M. Pai, C. Kirkpatrick, J. Stein, and M. Peifer, transitionsbyrepressingE-cadherinexpression,”NatureCell “Roles of the C terminus of armadillo in Wingless signaling Biology, vol. 2, no. 2, pp. 76–83, 2000. in Drosophila,” Genetics, vol. 153, no. 1, pp. 319–332, 1999. [45] K. Vleminckx, L. Vakaet Jr, M. Mareel, W. Fiers, and [29] B. Ciruna and J. Rossant, “FGF signaling regulates mesoderm F. Van Roy, “Genetic manipulation of E-cadherin expression cell fate speciﬁcation and morphogenetic movement at the byepithelial tumor cellsreveals aninvasion suppressorrole,” primitive streak,” Developmental Cell, vol. 1, no. 1, pp. 37–49, Cell, vol. 66, no. 1, pp. 107–119, 1991. 2001. [46] T.Brabletz,A.Jung,S.Reuetal.,“Variable-cateninexpression [30] N. Doumpas, F. Lampart, M. D. Robinson et al., “TCF/LEF in colorectal cancers indicates tumor progression driven by dependent and independent transcriptional regulation of thetumorenvironment,”ProceedingsoftheNationalAcademy Wnt/β-catenin target genes,” %e EMBO Journal, vol. 38, of Sciences, vol. 98, no. 18, pp. 10356–10361, 2001. [47] D. M. Bozhkova and E. G. Poryazova-Markova, “0e epi- no. 2, Article ID e98873, 2019. [31] A. Eger, A. Stockinger, J. Park et al., “β-Catenin and TGFβ thelial-mesenchymal transition, E-cadherin and tumor signalling cooperate to maintain a mesenchymal phenotype progression in ovarian serous tumors,” Folia Medica, vol. 61, after FosER-induced epithelial to mesenchymal transition,” no. 2, pp. 296–302, 2019. Oncogene, vol. 23, no. 15, pp. 2672–2680, 2004. [48] C. Ahluwalia, G. Bhuyan, R. Arora, and P. Sharma, “Epi- [32] S. Foulquier, E. P. Daskalopoulos, G. Lluri, thelial-mesenchymal transition in serous and mucinous K. C. M. Hermans, A. Deb, and W. M. Blankesteijn, “WNT epithelial tumors of the ovary,” Journal of Cancer Research signaling in cardiac and vascular disease,” Pharmacological and %erapeutics, vol. 15, no. 6, pp. 1309–1315, 2019. Reviews, vol. 70, no. 1, pp. 68–141, 2018. [49] S. H. Barghout, N. Zepeda, Z. Xu, H. Steed, C.-H. Lee, and Y. Fu, “Elevated β-catenin activity contributes to carboplatin [33] A. Mostowska, P. Pawlik, S. Sajdak et al., “An analysis of polymorphisms within the Wnt signaling pathway in rela- resistance in A2780cp ovarian cancer cells,” Biochemical and tionto ovarian cancerrisk in a polish population,”Molecular Biophysical Research Communications, vol. 468, no. 1-2, Diagnosis & %erapy, vol. 18, no. 1, pp. 85–91, 2014. pp. 173–178, 2015. [34] T. A. Gatcliﬀe, B. J. Monk, K. Planutis, and R. F. Holcombe, [50] A. B. Nagaraj, P. Joseph, O. Kovalenko et al., “Critical role of “Wnt signaling in ovarian tumorigenesis,” International Wnt/β-catenin signaling in driving epithelial ovarian cancer Journal of Gynecological Cancer, vol. 18, no. 5, pp. 954–962, platinum resistance,” Oncotarget, vol. 6, no. 27, pp. 23720–23734, 2015. [35] E. Krieghoﬀ, J. Behrens, and B. Mayr, “Nucleo-cytoplasmic [51] L. J. Wang and H. R. Shi, “Research on resveratrol inhibiting the growth of ovarian cancer cells and Wnt signaling distribution of β-catenin is regulated by retention,” Journal of Cell Science, vol. 119, no. 7, pp. 1453–1463, 2006. pathway by regulating SIRT1,” Chinese Traditional and [36] L. X. Zhong, Research on the Molecular Mechanism of Herbal Medicine, vol. 50, no. 3, pp. 675–680, 2019. Resveratrol against Ovarian Cancer, Dalian Medical University, [52] Z. Y. Hou, J. Gao, and Y. Wu, “Eﬀects of resveratrol on Dalian, China, 2015, https://kns.cnki.net/KCMS/detail/detail. proliferation activity, proliferation gene mRNA expression aspx?dbname�CDFDLAST2016&ﬁlename�1015625605.nh. and Wnt signaling pathway in ovarian cancer cells,” Chinese [37] C. Song, %e Expression and Clinical Signiﬁcance of EN2 and JournalofOncologicalSurgery, vol.12, no.1,pp. 63–66, 2020. β-catenin in Ovarian Cancer, Qingdao University, Dalian, [53] J.M.Gong,Y.Q.Zhou,andQ.Lin,“HydroxysaﬄoryellowA China, 2020, https://kns.cnki.net/KCMS/detail/detail.aspx? inhibits the growth of ovarian cancer through the Wnt/ β-catenin signaling pathway,” Journal of Medical Research, dbname�CMFD202101&ﬁlename�1020387425.nh. [38] Y. P. Sun, Z. H. Ni, and M. Z. Zhang, “Eﬀect and mechanism vol. 48, no. 10, pp. 131–134, 2019. of hydroxycamptothecin on proliferation and apoptosis of [54] C. Hu, Emodin Inhibits Epithelial-Mesenchymal Transition of lung cancer A549,” Shandong medicine, vol. 60, no. 5, Epithelial Ovarian Cancer Cells and its Mechanism, Shandong pp. 6–9, 2020. University, Jinan, China, 2016, https://kns.cnki.net/KCMS/ [39] B. Yao and Q. H. Zhang, “0e role of Wnt/β-catenin sig- detail/detail.aspx?dbname�CMFD201701&ﬁlename�1016158 naling pathway in the proliferation, migration and invasion 241.nh. of ovarian cancer stem cells,” Chinese Tissue Engineering [55] Y. Liu and J. X. Guo, “Oridonin inhibits the malignant Research, vol. 22, no. 25, pp. 4001–4006, 2018. behavior of human ovarian cancer cells and its mechanism,” Journal of Oncology 9 Modern Preventive Medicine, vol. 48, no. 1, pp. 139–143, [69] J. Breuss, A. Atanasov, and P. Uhrin, “Resveratrol and its 2021. eﬀects on the vascular system,” International Journal of [56] W. Q. Zeng, Q. Xu, and Y. Y. Xu, “Schisandrin B on the Molecular Sciences, vol. 20, no. 7, p. 1523, 2019. proliferation, apoptosis and Wnt/β-catenin signaling path- [70] Y.-Z. Mei, R.-X. Liu, D.-P. Wang, X. Wang, and C.-C. Dai, “Biocatalysis and biotransformation of resveratrol in mi- way of human ovarian cancer Skov3 cell line,” Journal of croorganisms,” Biotechnology Letters, vol. 37, no.1, pp. 9–18, Clinical Oncology, vol. 19, no. 7, pp. 589–593, 2014. [57] J. Z. Zhang, D. L. Ma, and S. H. Zhang, “Apigenin regulates [71] I. Baczko´ and P. E. Light, “Resveratrol and derivatives for the the inﬂuence of Wnt signaling pathway on the invasion of treatment of atrial ﬁbrillation,” Annals of the New York ovarian cancer cells,” Oncology Pharmacy, vol. 7, no. 3, Academy of Sciences, vol. 1348, no. 1, pp. 68–74, 2015. pp. 284–289, 2017. [72] H. Ao, W. Feng, and C. Peng, “Hydroxysaﬄor yellow A: a [58] C.-M. Lin, H.-H. Chen, C.-A. Lin, H.-C. Wu, J. J.-C. Sheu, promising therapeutic agent for a broad spectrum of dis- and H.-J. Chen, “Apigenin-induced lysosomal degradation eases,” Evidence-based Complementary and Alternative of β-catenin in Wnt/β-catenin signaling,” Scientiﬁc Reports, Medicine, vol. 2018, Article ID 8259280, 17 pages, 2018. vol. 7, no. 1, p. 372, 2017. [73] Y. M. Yuan, R. H. Wang, and S. X. Yang, “Research progress [59] L. F. Chen, J. Ren, and Y. Chen, “Eﬀects and mechanism of on the anti-tumor eﬀect of saﬄor yellow,” Chinese Journal of tea tree ﬂower saponins on the proliferation of ovarian Clinical Pharmacology, vol. 33, no. 5, pp. 478–480, 2017. cancer stem cell-like cells,” Journal of Zhejiang University [74] N. Wu, J. Li, H. Luo, D. Wang, and X. Bai, “Hydroxysaﬄor (Agriculture and Life Sciences), vol. 46, no. 6, pp. 667–676, yellow A promotes apoptosis via blocking autophagic ﬂux in liver cancer,” Biomedicine & Pharmacotherapy, vol. 136, [60] L. F. Chen, Inhibition and Mechanism of Tea Tree Flower Article ID 111227, 2021. Saponins on Human Ovarian Cancer Cells and %eir Stem [75] X. Dong, J. Fu, X. Yin et al., “Emodin: a review of its Cells, Zhejiang University, Hangzhou, China, 2020, https:// pharmacology, toxicity and pharmacokinetics,” Phytother- kns.cnki.net/KCMS/detail/detail.aspx?dbname�CMFD20210 apy Research, vol. 30, no. 8, pp. 1207–1218, 2016. 1&ﬁlename�1020314563.nh. [76] S.-Z. Lin, W.-T. Wei, H. Chen et al., “Antitumor activity of [61] R. Chen, Y. Su, and J. Liu, “0e eﬀect of icariin on the emodin against pancreatic cancer depends on its dual role: proliferation of ovarian cancer cells CAOV3 through the promotion of apoptosis and suppression of angiogenesis,” Wnt/β-catenin signaling pathway,” Journal of Medical Re- PLoS One, vol. 7, no. 8, Article ID e42146, 2012. search, vol. 48, no. 3, pp. 44–49, 2019. [77] Y. Zhang, S. Wang, M. Dai, J. Nai, L. Zhu, and H. Sheng, [62] L. Long and L. L. Tang, “Eﬀects of green tea extract epi- “Solubility and bioavailability enhancement of oridonin: a gallocatechin-3-gallate on the proliferation of human review,” Molecules, vol. 25, no. 2, p. 332, 2020. ovarian cancer HO-8910 cells and the expression of Wnt/ [78] D. Li, T. Han, J. Liao et al., “Oridonin, a promising ent- β-catenin signaling pathway related genes,” Chinese Journal kaurane diterpenoid lead compound,” International Journal of Biological Products, vol. 25, no. 09, pp. 1165–1170, 2012. of Molecular Sciences, vol. 17, no. 9, p. 1395, 2016. [63] C. F. Zhang, G. M. Yan, and Macron, “Research progress of [79] Y.Ding,C.Ding,N.Yeetal.,“Discoveryanddevelopmentof paeonol on anticancer eﬀects and mechanisms in the past natural product oridonin-inspired anticancer agents,” Eu- ﬁve years,” Journal of Liaoning University of Traditional ropeanJournalofMedicinalChemistry,vol.122,pp.102–117, Chinese Medicine, vol. 21, no. 10, pp. 158–161, 2019. [64] Q. N. Li, L. L. Wang, and J. M. Tang, “Experimental study of [80] M. I. Nasser, S. Zhu, C. Chen, M. Zhao, H. Huang, and paeonolinhibitingtheproliferationofhumanovariancancer P. Zhu, “A comprehensive review on schisandrin B and its A2780 cells by regulating the Wnt/β-catenin signaling biological properties,” Oxidative Medicine and Cellular pathway,” Chinese Journal of Practical Diagnosis and %er- Longevity, vol. 2020, Article ID 2172740, 13 pages, 2020. apy, vol. 31, no. 11, pp. 1062–1066, 2017. [81] C.-Y. Sun, J. Nie, Z.-L. Zheng et al., “Renoprotective eﬀect of [65] Y. L. Wang, X. G. Jia, and J. Zhu, “Experimental study of scutellarin on cisplatin-induced renal injury in mice: impact tetrandrine regulating the expression of miR-21 to inhibit on inﬂammation, apoptosis, and autophagy,” Biomedicine & epithelial-mesenchymal transition in ovarian cancer,” Pharmacotherapy, vol. 112, Article ID 108647, 2019. Shanghai Journal of Traditional Chinese Medicine, vol. 54, [82] W. L. Li, “Apigenin’s anti-tumor eﬀect and mechanism no. 8, pp. 71–76, 2020. research progress,” China Medical Herald, vol. 11, no. 21, [66] L. Jiang and R. Hou, “Tetrandrine reverses paclitaxel resis- pp. 165–168, 2014. tance in human ovarian cancer via inducing apoptosis, cell [83] L.-P. Chan, T.-H. Chou, H.-Y. Ding et al., “Apigenin induces cycle arrest through β-catenin pathway,” OncoTargets and apoptosis via tumor necrosis factor receptor- and Bcl-2- %erapy, vol. 13, pp. 3631–3639, 2020. mediated pathway and enhances susceptibility of head and [67] Y. Zhang, S. Chen, C. Wei, G. O. Rankin, X. Ye, and neck squamous cell carcinoma to 5-ﬂuorouracil and cis- Y. C. Chen, “Dietary compound proanthocyanidins from platin,” Biochimica et Biophysica Acta (BBA)-General Sub- Chinese bayberry (Myrica rubraSieb. et Zucc.) leaves at- jects, vol. 1820, no. 7, pp. 1081–1091, 2012. tenuate chemotherapy-resistant ovarian cancer stem cell [84] Y. Wang, N. Ren, G. O. Rankin et al., “Anti-proliferative traitsviatargeting the Wnt/β-catenin signaling pathway and eﬀect and cell cycle arrest induced by saponins extracted inducing G1 cell cycle arrest,” Food & Function, vol. 9, no.1, from tea (Camellia sinensis) ﬂower in human ovarian cancer pp. 525–533, 2018. cells,”JournalofFunctionalFoods,vol.37,pp.310–321,2017. [68] H.Zhu,X.Zou, S.Lin,X. Hu,andJ. Gao,“Eﬀectsof naringin [85] H. Matsuda, S. Nakamura, T. Morikawa, O. Muraoka, and on reversing cisplatin resistance and the Wnt/β-catenin M. Yoshikawa, “New biofunctional eﬀects of the ﬂower buds pathway in human ovarian cancer SKOV3/CDDP cells,” of Camellia sinensis and its bioactive acylated oleanane-type Journal of International Medical Research, vol. 48, no. 10, triterpene oligoglycosides,” Journal of Natural Medicines, Article ID 030006051988786, 2020. vol. 70, no. 4, pp. 689–701, 2016. 10 Journal of Oncology [86] T. Wu, S. Wang, J. Wu et al., “Icaritin induces lytic cyto- toxicity in extranodal NK/T-cell lymphoma,” Journal of Experimental&ClinicalCancerResearch, vol. 34, no.1, p.17, [87] C. Chu, J. Deng, Y. Man, and Y. Qu, “Green tea extracts epigallocatechin-3-gallate for diﬀerent treatments,” BioMed Research International, vol. 2017, Article ID 5615647, 9 pages, 2017. [88] S. D. Rao and K. Pagidas, “Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells,” Anticancer Re- search, vol. 30, no. 7, pp. 2519–2523, 2010. [89] S.-S. Li, G.-F. Li, L. Liu et al., “Evaluation of paeonol skin- target delivery from its microsponge formulation: in vitro skin permeation and in vivo microdialysis,”PLoSOne, vol. 8, no. 11, Article ID e79881, 2013. [90] T. Liu, X. Liu, and W. Li, “Tetrandrine, a Chinese plant- derived alkaloid, is a potential candidate for cancer che- motherapy,” Oncotarget, vol. 7, no. 26, pp. 40800–40815, [91] N. Bhagya and K. R. Chandrashekar, “Tetrandrine-a mole- cule of wide bioactivity,” Phytochemistry, vol. 125, pp. 5–13, [92] J. Xu, X. Wang, and L. Lei, “Research progress of proan- thocyanidins in the prevention and control of secretory diarrhea,” Chinese Journal of Animal Husbandry, vol. 57, no. 4, pp. 44–48, 2021. [93] C. Sun, K. Mcintyre, A. Saleem, P. S. Haddad, and J. T. Arnason, “0e relationship between antiglycation ac- tivity and procyanidin and phenolic content in commercial grape seed products,” Canadian Journal of Physiology and Pharmacology, vol. 90, no. 2, pp. 167–174, 2012. [94] K. F. Daughenbaugh, J. Holderness, J. C. Graﬀ et al., “Contribution of transcript stability to a conserved pro- cyanidin-induced cytokine response in cδ T cells,” Genes & Immunity, vol. 12, no. 5, pp. 378–389, 2011. [95] F.Y. Zhang, X. Y. Zhao, and D. L. Zhang, “Research progress on anti-tumor eﬀects and mechanisms of proanthocyani- dins,” Chongqing Medical Journal, vol. 41, no. 27, pp. 2887–2889, 2012. [96] D.Dong,L.Xu,L.Yin,Y.Qi,andJ.Peng,“Naringinprevents carbon tetrachloride-induced acute liver injury in mice,” Journal of Functional Foods, vol. 12, pp. 179–191, 2015. [97] A. Yoshinaga, N. Kajiya, K. Oishi et al., “NEU3 inhibitory eﬀect of naringin suppresses cancer cell growth by attenu- ation of EGFR signaling through GM3 ganglioside accu- mulation,” European Journal of Pharmacology, vol. 782, pp. 21–29, 2016. [98] W. J. Yang, L. Wang, and R. Sun, “Eﬀects of diﬀerent concentrations of naringin on proliferation and COX-2 expression of human cervical cancer HeLa cells in vitro,” ChineseJournalofimmunology, vol. 32,no. 8, pp.1200–1203, [99] Y. Wen, C. Y. Liu, and Q. Q. Xing, “0e eﬀect of naringin on the proliferation, apoptosis and migration of human ovarian cancer cell SKOV3,” Journal of Clinical Oncology, vol. 22, no. 12, pp. 1085–1090, 2017. [100] V.H.L.Nguyen,R.Hough,S.Bernaudo,andC.Peng,“Wnt/ β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis,” Journal of Ovarian Research, vol. 12, no. 1, p. 122, 2019.

Journal

Journal of Oncology – Hindawi Publishing Corporation

Published: Dec 6, 2021

References

Cancer statistics, 2020,

R. L. Siegel, K. D. Miller, and A. Jemal
The influence of birth cohort and calendar period on global trends in ovarian cancer incidence,

C. J. Cabasag, M. Arnold, J. Butler et al.
Ovarian cancer statistics, 2018,

L. A. Torre, B. Trabert, C. E. DeSantis et al.
Epithelial ovarian cancer: evolution of management in the era of precision medicine,

S. Lheureux, M. Braunstein, and A. M. Oza
Advances in tumor markers of ovarian cancer for early diagnosis,

W. Zhang, P. Lei, X. Dong, and X. Men
First-line treatment of women with advanced ovarian cancer: focus on bevacizumab,

C. Marchetti, L. Muzii, A. Romito, and P. Benedetti Panici
PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer,

H. Li, J. Zeng, and K. Shen
Notch3 pathway alterations in ovarian cancer,

W. Hu, T. Liu, C. Ivan et al.
Kanoniczna ścieżka sygnałowa Wnt,

R. Kleszcz
Wnt signaling in osteosarcoma,

A. Singla, J. Wang, R. Yang, D. S. Geller, D. M. Loeb, and B. H. Hoang
Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome,

R. Nusse and H. E. Varmus
The Drosophila homology of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless,

F. Rijsewijk, M. Schuermann, E. Wagenaar, P. Parren, D. Weigel, and R. Nusse
β-catenin: a key mediator of Wnt signaling,

K. Willert and R. Nusse
Wnt signaling cascade in dendritic cells and regulation of anti-tumor immunity,

A. Suryawanshi, M. S. Hussein, P. D. Prasad, and S. Manicassamy
Wnt signaling: pathogen incursion and immune defense,

S. Jati, T. R. Sarraf, D. Naskar, and M. Sen
Wnt signaling in cancer,

T. Zhan, N. Rindtorff, and M. Boutros
EZH2 impairs human dental pulp cell mineralization via the Wnt/β-catenin pathway,

B. Li, F. Yu, F. Wu et al.
Modulating the Wnt signaling pathway with small molecules,

F. H. Tran and J. J. Zheng
Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling,

M. Takeichi
E-cadherin: its dysregulation in carcinogenesis and clinical implications,

S. H. M. Wong, C. M. Fang, L.-H. Chuah, C. O. Leong, and S. C. Ngai
E-cadherin junctions as active mechanical integrators in tissue dynamics,

T. Lecuit and A. S. Yap
Modulation of E-cadherin function and dysfunction by N-glycosylation,

S. S. Pinho, R. Seruca, F. Gärtner et al.
The cell-cell adhesion molecule E-cadherin,

F. Van Roy and G. Berx
E-cadherin in contact inhibition and cancer,

A. M. Mendonsa, T.-Y. Na, and B. M. Gumbiner
Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus,

F. Fagotto, N. Funayama, U. Gluck, and B. M. Gumbiner
E-cadherin suppresses cellular transformation by inhibiting β-catenin signaling in an adhesion-independent manner,

C. J. Gottardi, E. Wong, and B. M. Gumbiner
Roles of the C terminus of armadillo in Wingless signaling in Drosophila,

R. T. Cox, L.-M. Pai, C. Kirkpatrick, J. Stein, and M. Peifer
FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak,

B. Ciruna and J. Rossant
TCF/LEF dependent and independent transcriptional regulation of Wnt/β‐catenin target genes,

N. Doumpas, F. Lampart, M. D. Robinson et al.
β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition,

A. Eger, A. Stockinger, J. Park et al.
WNT signaling in cardiac and vascular disease,

S. Foulquier, E. P. Daskalopoulos, G. Lluri, K. C. M. Hermans, A. Deb, and W. M. Blankesteijn
An analysis of polymorphisms within the Wnt signaling pathway in relation to ovarian cancer risk in a polish population,

A. Mostowska, P. Pawlik, S. Sajdak et al.
Wnt signaling in ovarian tumorigenesis,

T. A. Gatcliffe, B. J. Monk, K. Planutis, and R. F. Holcombe
Nucleo-cytoplasmic distribution of β-catenin is regulated by retention,

E. Krieghoff, J. Behrens, and B. Mayr
Effect and mechanism of hydroxycamptothecin on proliferation and apoptosis of lung cancer A549,

Y. P. Sun, Z. H. Ni, and M. Z. Zhang
The role of Wnt/β-catenin signaling pathway in the proliferation, migration and invasion of ovarian cancer stem cells,

B. Yao and Q. H. Zhang
Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile,

A. Latifi, K. Abubaker, N. Castrechini et al.
E-cadherin/β-catenin complex and the epithelial barrier,

X. Tian, Z. Liu, B. Niu et al.
E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium,

N. Auersperg, J. Pan, B. D. Grove et al.
Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced,

E. D. Hay and A. Zuk
The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression,

A. Cano, M. A. Pérez-Moreno, I. Rodrigo et al.
Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role,

K. Vleminckx, L. Vakaet Jr, M. Mareel, W. Fiers, and F. Van Roy
Variable -catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment,

T. Brabletz, A. Jung, S. Reu et al.
The epithelial-mesenchymal transition, E-cadherin and tumor progression in ovarian serous tumors,

D. M. Bozhkova and E. G. Poryazova-Markova
Epithelial-mesenchymal transition in serous and mucinous epithelial tumors of the ovary,

C. Ahluwalia, G. Bhuyan, R. Arora, and P. Sharma
Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells,

S. H. Barghout, N. Zepeda, Z. Xu, H. Steed, C.-H. Lee, and Y. Fu
Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance,

A. B. Nagaraj, P. Joseph, O. Kovalenko et al.
Research on resveratrol inhibiting the growth of ovarian cancer cells and Wnt signaling pathway by regulating SIRT1,

L. J. Wang and H. R. Shi
Effects of resveratrol on proliferation activity, proliferation gene mRNA expression and Wnt signaling pathway in ovarian cancer cells,

Z. Y. Hou, J. Gao, and Y. Wu
Hydroxysafflor yellow A inhibits the growth of ovarian cancer through the Wnt/β-catenin signaling pathway,

J. M. Gong, Y. Q. Zhou, and Q. Lin
Oridonin inhibits the malignant behavior of human ovarian cancer cells and its mechanism,

Y. Liu and J. X. Guo
Schisandrin B on the proliferation, apoptosis and Wnt/β-catenin signaling pathway of human ovarian cancer Skov3 cell line,

W. Q. Zeng, Q. Xu, and Y. Y. Xu
Apigenin regulates the influence of Wnt signaling pathway on the invasion of ovarian cancer cells,

J. Z. Zhang, D. L. Ma, and S. H. Zhang
Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling,

C.-M. Lin, H.-H. Chen, C.-A. Lin, H.-C. Wu, J. J.-C. Sheu, and H.-J. Chen
Effects and mechanism of tea tree flower saponins on the proliferation of ovarian cancer stem cell-like cells,

L. F. Chen, J. Ren, and Y. Chen
The effect of icariin on the proliferation of ovarian cancer cells CAOV3 through the Wnt/β-catenin signaling pathway,

R. Chen, Y. Su, and J. Liu
Effects of green tea extract epigallocatechin-3-gallate on the proliferation of human ovarian cancer HO-8910 cells and the expression of Wnt/β-catenin signaling pathway related genes,

L. Long and L. L. Tang
Research progress of paeonol on anticancer effects and mechanisms in the past five years,

C. F. Zhang, G. M. Yan, and Macron
Experimental study of paeonol inhibiting the proliferation of human ovarian cancer A2780 cells by regulating the Wnt/β-catenin signaling pathway,

Q. N. Li, L. L. Wang, and J. M. Tang
Experimental study of tetrandrine regulating the expression of miR-21 to inhibit epithelial-mesenchymal transition in ovarian cancer,

Y. L. Wang, X. G. Jia, and J. Zhu
Tetrandrine reverses paclitaxel resistance in human ovarian cancer via inducing apoptosis, cell cycle arrest through β-catenin pathway,

L. Jiang and R. Hou
Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubraSieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traitsviatargeting the Wnt/β-catenin signaling pathway and inducing G1 cell cycle arrest,

Y. Zhang, S. Chen, C. Wei, G. O. Rankin, X. Ye, and Y. C. Chen
Effects of naringin on reversing cisplatin resistance and the Wnt/β-catenin pathway in human ovarian cancer SKOV3/CDDP cells,

H. Zhu, X. Zou, S. Lin, X. Hu, and J. Gao
Resveratrol and its effects on the vascular system,

J. Breuss, A. Atanasov, and P. Uhrin
Biocatalysis and biotransformation of resveratrol in microorganisms,

Y.-Z. Mei, R.-X. Liu, D.-P. Wang, X. Wang, and C.-C. Dai
Resveratrol and derivatives for the treatment of atrial fibrillation,

I. Baczkó and P. E. Light
Hydroxysafflor yellow A: a promising therapeutic agent for a broad spectrum of diseases,

H. Ao, W. Feng, and C. Peng
Research progress on the anti-tumor effect of safflor yellow,

Y. M. Yuan, R. H. Wang, and S. X. Yang
Hydroxysafflor yellow A promotes apoptosis via blocking autophagic flux in liver cancer,

N. Wu, J. Li, H. Luo, D. Wang, and X. Bai
Emodin: a review of its pharmacology, toxicity and pharmacokinetics,

X. Dong, J. Fu, X. Yin et al.
Antitumor activity of emodin against pancreatic cancer depends on its dual role: promotion of apoptosis and suppression of angiogenesis,

S.-Z. Lin, W.-T. Wei, H. Chen et al.
Solubility and bioavailability enhancement of oridonin: a review,

Y. Zhang, S. Wang, M. Dai, J. Nai, L. Zhu, and H. Sheng
Oridonin, a promising ent-kaurane diterpenoid lead compound,

D. Li, T. Han, J. Liao et al.
Discovery and development of natural product oridonin-inspired anticancer agents,

Y. Ding, C. Ding, N. Ye et al.
A comprehensive review on schisandrin B and its biological properties,

M. I. Nasser, S. Zhu, C. Chen, M. Zhao, H. Huang, and P. Zhu
Renoprotective effect of scutellarin on cisplatin-induced renal injury in mice: impact on inflammation, apoptosis, and autophagy,

C.-Y. Sun, J. Nie, Z.-L. Zheng et al.
Apigenin’s anti-tumor effect and mechanism research progress,

W. L. Li
Apigenin induces apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin,

L.-P. Chan, T.-H. Chou, H.-Y. Ding et al.
Anti-proliferative effect and cell cycle arrest induced by saponins extracted from tea (Camellia sinensis) flower in human ovarian cancer cells,

Y. Wang, N. Ren, G. O. Rankin et al.
New biofunctional effects of the flower buds of Camellia sinensis and its bioactive acylated oleanane-type triterpene oligoglycosides,

H. Matsuda, S. Nakamura, T. Morikawa, O. Muraoka, and M. Yoshikawa
Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma,

T. Wu, S. Wang, J. Wu et al.
Green tea extracts epigallocatechin-3-gallate for different treatments,

C. Chu, J. Deng, Y. Man, and Y. Qu
Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells,

S. D. Rao and K. Pagidas
Evaluation of paeonol skin-target delivery from its microsponge formulation: in vitro skin permeation and in vivo microdialysis,

S.-S. Li, G.-F. Li, L. Liu et al.
Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy,

T. Liu, X. Liu, and W. Li
Tetrandrine-a molecule of wide bioactivity,

N. Bhagya and K. R. Chandrashekar
Research progress of proanthocyanidins in the prevention and control of secretory diarrhea,

J. Xu, X. Wang, and L. Lei
The relationship between antiglycation activity and procyanidin and phenolic content in commercial grape seed products,

C. Sun, K. Mcintyre, A. Saleem, P. S. Haddad, and J. T. Arnason
Contribution of transcript stability to a conserved procyanidin-induced cytokine response in γδ T cells,

K. F. Daughenbaugh, J. Holderness, J. C. Graff et al.
Research progress on anti-tumor effects and mechanisms of proanthocyanidins,

F. Y. Zhang, X. Y. Zhao, and D. L. Zhang
Naringin prevents carbon tetrachloride-induced acute liver injury in mice,

D. Dong, L. Xu, L. Yin, Y. Qi, and J. Peng
NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation,

A. Yoshinaga, N. Kajiya, K. Oishi et al.
Effects of different concentrations of naringin on proliferation and COX-2 expression of human cervical cancer HeLa cells in vitro,

W. J. Yang, L. Wang, and R. Sun
The effect of naringin on the proliferation, apoptosis and migration of human ovarian cancer cell SKOV3,

Y. Wen, C. Y. Liu, and Q. Q. Xing
Wnt/β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis,

V. H. L. Nguyen, R. Hough, S. Bernaudo, and C. Peng

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

Plant-Derived Chinese Medicine Monomers on Ovarian Cancer via the Wnt/β-Catenin Signaling Pathway: Review of Mechanisms and Prospects

References

Abstract

Journal

Recommended Articles

References

Our policy towards the use of cookies