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Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns, Mechanisms, and Interactions

Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns,... Hindawi Journal of Oncology Volume 2021, Article ID 5519720, 15 pages https://doi.org/10.1155/2021/5519720 Review Article Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns, Mechanisms, and Interactions 1 1 2 3,4 Suaidah Ramli , Maw Shin Sim , Rhanye M. Guad , Subash C. B Gopinath , 5 6 6 Vetriselvan Subramaniyan , Shivkanya Fuloria , Neeraj K. Fuloria , 7 8 9 Ker Woon Choy , Sohel Rana , and Yuan Seng Wu Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Malaysia Department of Biomedical Science and &erapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia School of Bioprocess Engineering, Universiti Malaysia Perlis, Arau 02600, Perlis, Malaysia Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar 01000, Perlis, Malaysia Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor 42610, Malaysia Faculty of Pharmacy, AIMST University, Bedong, Kedah 08100, Malaysia Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Shah Alam, Sungai Buloh 47000, Selangor, Malaysia Department of Pharmacy, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore-7400, Bangladesh Department of Biochemistry, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor 42610, Malaysia Correspondence should be addressed to Yuan Seng Wu; sengwu_21@yahoo.com Received 29 January 2021; Revised 15 March 2021; Accepted 26 March 2021; Published 12 April 2021 Academic Editor: Dan Zhao Copyright © 2021 Suaidah Ramli et al. ,is 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. ,e rising trend of gastrointestinal (GI) cancer has become a global burden due to its aggressive nature and poor prognosis. Long noncoding RNAs (lncRNAs) have recently been reported to be overexpressed in different GI cancers and may contribute to cancer progression and chemoresistance. ,ey are featured with more than 200 nucleotides, commonly polyadenylated, and lacking an open reading frame. LncRNAs, particularly urothelial carcinoma-associated 1 (UCA1), are oncogenes involved in regulating cancer progression, such as cell proliferation, invasion, migration, and chemoresistance, particularly in GI cancer. ,is review was aimed to present an updated focus on the molecular regulatory roles and patterns of lncRNA UCA1 in progression and che- moresistance of different GI cancers, as well as deciphering the underlying mechanisms and its interactions with key molecules involved, together with a brief presentation on its diagnostic and prognostic values. ,e regulatory roles of lncRNA UCA1 are implicated in esophageal cancer, gastric cancer, pancreatic cancer, hepatobiliary cancer, and colorectal cancer, where they shared similar molecular mechanisms in regulating cancer phenotypes and chemoresistance. Comparatively, gastric cancer is the most intensively studied type in GI cancer. LncRNA UCA1 is implicated in biological roles of different GI cancers via interactions with various molecules, particularly microRNAs, and signaling pathways. In conclusion, lncRNA UCA1 is a potential molecular target for GI cancer, which may lead to the development of a novel chemotherapeutic agent. Hence, it also acts as a potential diagnostic and prognostic marker for GI cancer patients. 2 Journal of Oncology chemoresistance in BLS-211 BC cells [13]. In the last decade, 1. Introduction the regulatory roles of lncRNAs have been intensively in- Gastrointestinal (GI) cancer has become one of the major vestigated in which most studies have suggested that the challenges in the health sector in recent decades. GI cancer is mechanistic pathways underlying the regulatory roles of a group of cancers that affect the GI tract, such as esophagus, lncRNA UCA1. In this context, its interaction with the key stomach, gallbladder, liver, biliary tract, small intestine, and genes or proteins is the key causative factor that leads to the large intestine [1, 2]. In 2018, GI cancer contributed 26% development of GI cancer. among all cancer cases and 35% of cancer-causing death ,erefore, this review aims to provide a detailed insight into worldwide [3]. ,ere are five major GI cancers, namely, the regulatory roles of lncRNA UCA1 in GI cancer progression gastric cancer (GC), hepatobiliary cancer, esophageal cancer and chemoresistance, as evidenced in preclinical and clinical (EC), pancreatic cancer (PC), and colorectal cancer (CRC), studies. In addition, it also discusses various molecular accounting for approximately 1 million, 840,000, 570,000, mechanisms underlie and the key molecules involved, intending 460,000, and 1.7 million new cases were reported in 2018, to present its potential as a novel molecular target, as well as a respectively [4]. Comparatively, EC, GC, and liver cancer diagnostic and prognostic marker for GI cancer. (LC) are predominant in Asian population, whereas CRC shows more incidence in Europe and North America [3]. 2. LncRNA UCA1 Apart from that, GI cancer shows a reduced 5-year survival rate and a poor prognosis at the late stage of cancer [5]. Over the past few years, there is a bloom of transcriptome Generally, several factors have been reported to be the studies associated with the advancement in RNA sequencing contributing risk factors for GI cancer, including tobacco technology, which enables the view of the complexity of smoking, alcohol consumption, diet, and obesity and in- eukaryotic gene expression [20]. ,is advanced technology fections, such as Helicobacter pylori in GC and hepatitis virus leads to the discovery of lncRNAs [21]. More than 98% of the in LC [3, 6, 7]. genomes transcribed into ncRNAs are categorized, either as With the recent advancement in RNA sequencing structural RNAs or regulatory RNAs, where lncRNA is technology transcriptome knowledge, there are increased classified under regulatory RNAs [22]. LncRNAs are dis- interests in long noncoding RNAs (lncRNAs) as they play covered as an important new player in cell differentiation an important role in tumorigenesis, particularly gene and development, as well as organogenesis and genomic regulation [8, 9]. LncRNA is characterized by possessing imprinting [23, 24]. Additionally, most lncRNAs, including more than 200 nucleotides that would not be translated lncRNA UCA1, are much like mRNAs where they are into protein [10]. It can be found in both nucleus and transcribed by RNA polymerase II with similar chromatin cytoplasm where the chromatin remodeling, transcrip- states to mRNAs, and they usually 5′capped, spliced, and tional regulation, and RNA processing take place in the polyadenylated [25, 26]. ,e biogenesis of lncRNA UCA1 is nucleus, while its interaction with mRNA and signaling illustrated in Figure 1. pathway occurs in the cytoplasm [11, 12]. One of the re- It has been reported that several lncRNAs participate in ported cancer-related lncRNAs is urothelial carcinoma- the special processing events, including DNA organization. associated 1 (UCA1) that was first discovered in 2006 as it In this event, genomic DNA is packed in the nucleus with a was found to be overexpressed in bladder cancer (BC) cells, special genomic organization, depending on both histone a cancer close to but not belonged to GI cancer [13]. It and chromatin modifications that are regulated by epige- belongs to human endogenous retrovirus H family and is netic complexes and affect the transcriptional activity located at 19p13.12 of the chromosomes positive-strand [27, 28]. For instance, lncRNA metastasis-associated lung with three exons and two introns [13]. To date, three adenocarcinoma transcript 1 (MALAT1) and lncRNA nu- lncRNA UCA1 isoforms produced by RNA splicing have clear enriched abundant transcript 1 (NEAT1) are localized been discovered, and each of them with different sizes, at the nuclear speckles and nuclear paraspeckles, respec- including 1.4, 2.2, and 2.7 kb [14, 15]. Among them, 1.4 kb tively, after processing at 3′ ends by RNA polymerase II to lncRNA UCA1 is the most assessed and abundant isoform, form tRNA-like small RNA products and mature lncRNAs while 2.2 kb isoform is relatively more participated in [25, 29, 30]. However, the exact DNA organization for chemoresistance [14]. For instance, Wang et al. showed lncRNA UCA1 remains to be confirmed. Functionally, that lncRNA UCA1 significantly associated with cancer lncRNAs are involved in chromatin and epigenetic modi- chemoresistance toward cisplatin, gemcitabine, 5-fluoro- fications [31, 32]. LncRNA UCA1 also acts as an miRNA uracil, tamoxifen, and imatinib. Interestingly, the che- decoy and miRNA sponge, which sequester miRNA intra- mosensitivity of these drugs was significantly increased cellularly and compete with other genes for miRNA binding, when lncRNA UCA1 was silenced [16]. leading to an increased level of miRNA target gene ex- Apart from these, lncRNA UCA1 has been detected to be pression [1, 33]. overexpressed in various cancers, particularly GI cancers, Furthermore, lncRNA has also shown to play an im- such as CRC, esophageal squamous cell carcinoma (ESCC), portant role in embryogenesis where it has been identified to hepatocellular carcinoma (HCC), and GC [17–19]. Among be upregulated after 28 weeks of gestational in the tissue of lncRNAs, lncRNA UCA1 has been demonstrated to have heart, urinary bladder, and uterus, but downregulation is significant regulatory roles in cancer progression, including detected in liver, kidney, lung, spleen, intestine, stomach, cell proliferation, invasion, migration and metastasis, and skin, and cervix. In adult tissues, lncRNA UCA1 expression Journal of Oncology 3 cell nucleus and myelocytomatosis proto-oncogene (C- is relatively conserved at a low expression level, except for heart, spleen, and placenta [34]. In short, the ideal ex- myc), which is a target protein of Wnt signaling pathway in regulating cell cycle. ,is action ultimately reduced cancer pression of lncRNA UCA1 is remarkably essential for cell growth and development, particularly in embryogenesis cell proliferation, migration, and invasion [40]. Similarly, stage. Zhu et al. also demonstrated that lncRNA UCA1 was lowly expressed in EC tissues and plasma exosomes, which is a lipid-bilayer extracellular vesicle used as a cargo system for 3. Molecular Regulatory Roles, Patterns, various molecules, including lncRNAs, for implicating in the Mechanisms, and Interactions of LncRNA pathogenesis of many diseases, including cancer, by regu- UCA1 in Different Gastrointestinal Cancers lating intercellular communication. ,ey specifically found that exosomal lncRNA UCA1 could act as a growth inhibitor It has been reported that high expression levels of lncRNA in EC as its overexpression inhibited cell proliferation, UCA1 are detected in GI cancer cells [35, 36]. ,us, lncRNAs migration, invasion, and colony formation significantly, as may play an important role for GI tumorigenesis. ,e well as tumor growth in vivo via direct targeting of high positive association of lncRNA UCA1 with the overall levels of miR-613 [41]. It also acts as a potent diagnostic survival of GI cancer patients was revealed in a meta-analysis biomarker for EC, with great sensitivity (86.7%) and spec- [35]. ,e pooled result of 14 studies indicated that poor ificity (70.2%) [41]. However, these findings need to be overall survival in patients with digestive malignancies was further assessed as there is increasing evidence showing that associated with lncRNA UCA1 overexpression [35]. Since lncRNA UCA1 acts as an oncogenic lncRNA instead of then, different studies were conducted to further discover having tumor-suppressing function. Taken together, further the association between GI cancer and lncRNA UCA1 as well molecular studies of lncRNA UCA1 should be conducted to as identify the possible mechanisms responsible for GI elucidate its associated molecular mechanisms of regulatory cancer progression. In this review, the expression pattern, roles in EC clearly. regulatory roles and patterns, mechanistic pathways, and interactions of key molecules that are associated with lncRNA UCA1 in GI cancer progression and chemo- 3.2. Gastric Cancer. GC is one of GI cancers that contribute resistance, including EC, GC, hepatobiliary cancer, PC, and to high mortality due to late diagnosis [3, 77]. Intriguingly, CRC, are summarized (Table 1). A brief insight of the po- Gao et al. suggested that lncRNA UCA1 could be a potential tential role of lncRNA UCA1 as a diagnostic and prognostic diagnostic and biomarker target in the early stage of GC, marker, wherever applicable in different GI cancers, is also owing to the fact that highly expressed lncRNA UCA1 can be presented. ,e interaction of lncRNA UCA1 that affects the easily found in the plasma of GC patients and therefore target gene expression of miRNAs and activation of pivotal provides simplicity for sample extraction [42]. Similarly, it signaling pathway are illustrated in Figures 2 and 3, has also been discovered that lncRNA UCA1 is overex- respectively. pressed in both GC tumor and cell lines [43]. Moreover, it was also reported to play a role in GC cell migration and invasion via the induction of epithelial-mesenchymal 3.1. Esophageal Cancer. In ESCC patients, the most pre- transition (EMT) by competitively binding to miR-203, dominant deadly types of EC, lncRNA UCA1 has been reported to be overexpressed and contributed to poor prognosis [37]. increasing the expression of its target protein, Zinc Finger E-Box Binding Homeobox 2 (ZEB2) [44]. Jiao et al. showed that lncRNA UCA1 was strongly associated with EC cell proliferation by functioning as a competing en- In addition to miR-203, lncRNA UCA1 also interacts with miR-495-3p, supporting the role of UCA1 acting as a dogenous RNA (ceRNA) to regulate the expression of Sry- related high-mobility group box 4 (Sox4), a target protein of ceRNA [45]. Sun et al. reported that lncRNA UCA1 ex- pression could be regulated by special AT-rich-binding lncRNA UCA1 [38]. Additionally, lncRNA UCA1 also can protein 1 (SATB1), which was involved in chromatin directly interact with miR-204 to reduce miR-204-mediated modification in both MKN-45 and BGC-823 GC cells [45]. Sox4 degradation; thus, Sox4 can exert its biological role as a However, lncRNA UCA1 only regulated the protein levels tumor-promoting protein to stimulate EC progression [38]. of SATB1 in MKN-45 GC cells but not in BGC-823 cells Apart from that, overexpressed lncRNA UCA1 could also [45]. ,us, further investigation is required to discover the promote cell proliferation and metastasis by enhancing aerobic glycolysis through Warburg effect [39]. ,ese happened when rationale for obtaining such findings. Similarly, lncRNA UCA1 has also found to regulate lncRNA UCA1 sequestered miR-203, which then increased the levels of hexokinase 2 (HXK2) [39]. miR-590-3p expression that results in the activation of cAMP-responsive element-binding protein 1 (CREB1), Despite several studies have reported a positive corre- lation between overexpressed lncRNA UCA1 and tumor which is an oncogenic protein [46]. In addition, it plays a role in suppressing the immune system of GC cells by progression; however, contradictory findings were reported. elevating the expression of programmed death-1 ligand-1 For instance, Wang et al. discovered that overexpression of (PDL1) via sponging miR-193a and miR-214 [47]. In lncRNA UCA1 suppressed ESCC cell growth via the inhi- addition, Wang et al. also reported that lncRNA UCA1 bition of Wnt signaling pathway by suppressing β-catenin could sponge other miRNAs, for instance, miR-26a and activity [40]. ,ey claimed that lncRNA UCA1 could reduce miR-26b, thereby reducing their expression levels [47]. the expression of active β-catenin protein expression in the 4 Journal of Oncology rapamycin (p-mTOR), and ribosomal protein S6 kinase (S6K), RNA polymerase II while reducing the eukaryotic translation initiation factor 4E (EIF4E) protein levels in GC cells [49]. Consequently, the regulation of these proteins promoted GC cell growth and DNA proliferation [49]. ,is finding showed that lncRNA UCA1 could regulate multiple proteins involved in a signaling pathway. Transcription On the other hand, Wang et al. reported that specificity protein 1 (SP1) promoted the expression of lncRNA UCA1 in GC cells by binding to the core promoter of UCA1 [50]. ,e expressed lncRNA UCA1 was then activated AKT/GSK- RNA polymerase II 3 B/cyclin D1 axis by interacting with enhancer of zeste homolog 2 (EZH2), a histone methyltransferase [50]. Meanwhile, the interaction of lncRNA UCA1 enhanced EZH2 expression, which subsequently elevated the expres- sion of cyclin D1 to promote cell cycle [50]. ,ese findings Post-transcriptional supported the previous hypothesis that the association of processing lncRNA UCA1 in regulating other genes via epigenetic modification, which is histone modification in this case. ,e AAAAAA association of lncRNA UCA1 with AKT/GSK-3B/cyclin D1 was also identified in HCC [60]. Mature lncRNA UCAl In addition to EMT, lncRNA UCA1 can induce GC Figure 1: Biogenesis of lncRNA UCA1. LncRNA UCA1 is pro- metastasis by regulating G protein-coupled receptor kinase 2 duced by transcriptional process mediated by RNA polymerase II (GRK2) degradation and Casitas B-lineage Lymphoma (Cbl- from DNA template. It then undergoes special posttranscriptional c)-mediated ubiquitination, resulting in the activation of processing events, including 5′-capping, splicing, polyadenylation, extracellular-signal-regulated kinase (ERK)/matrix metal- and chemical base modification, to become a mature form. loproteinase-9 (MMP-9) signaling pathway [51]. Wang et al. demonstrated that lncRNA UCA1 interacted with GRK2 and ,is finding indicated that lncRNA UCA1 could function led to the exposure of GRK2 ubiquitination sites toward Cbl- as an miRNA sponge to reduce miRNA expression in the c for its degradation [51]. Consequently, the degraded GRK2 cells, subsequently reducing its inhibitory effects on the activated ERK/MMP-9 signaling pathway, which increased target protein. On the other hand, reduced ki-67 protein MMP-9 protein levels, to promote cell membrane degra- levels and increased levels of cleaved poly [ADP-ribose] dation, facilitating cancer cell migration and invasion [51]. polymerase 1 (PARP1) and cleaved caspase 3 were ob- ,is finding showed that lncRNA UCA1 could regulate the served in GC cells after lncRNA UCA1 silencing [47]. level of another protein by direct binding for degradation. However, the exact mechanism of lncRNA UCA1 in LncRNA UCA1 also plays a prominent role in chemo- regulating ki-67, PARP1, and caspase 3 is unknown, and resistance via miRNA signaling. For instance, the silenced further confirmation is required, particularly in identi- lncRNA UCA1 could upregulate the mRNA levels of miR- fying miRNAs or proteins associated with the regulation 27b and lead to reduced IC of doxorubicin, cisplatin, and of lncRNA UCA1. 5-fluorouracil, as well as promoting doxorubicin-induced In addition, Zuo et al. demonstrated that the induction apoptosis in doxorubicin-resistance SGC-7901 GC cells [52]. of high lncRNA UCA1 expression in GC cells was mediated In other words, the reduction of lncRNA UCA1 expression by transforming growth factor β1 (TGF-β1) [48]. ,e could improve the chemosensitivity of chemotherapeutic overexpressed lncRNA UCA1 consequently promoted EMT agents, at least for doxorubicin, cisplatin, and 5-fluorouracil by regulating the expression levels of EMT-related proteins, in GC therapy. Correspondingly, Cheng et al. reported that such as E-cadherin, vimentin, snail, and zonula occludens-1 lncRNA UCA1 silencing enhanced GC chemosensitivity (ZO-1) [48]. For instance, the mRNA levels of epithelial cell toward cisplatin by regulating the expression of miR-513a- markers, such as E-cadherin and ZO-1, were reduced, while 3p and Cytochrome P450 1B1 (CYP1B1) [53]. an elevation was observed for mesenchymal cell markers, Chemoresistance is also affected by cancer microenvi- namely vimentin and snail [48]. ,is finding indicated that ronment, such as hypoxic microenvironment, that claims to apart from regulating other genes or proteins, lncRNA block the exposure of chemotherapeutic agents to cancer UCA1 also can be regulated by other genes or proteins. cells [54]. Yang et al. reported that GC cells could survive in Meanwhile, lncRNA UCA1 has also been reported to the hypoxic environment via the interaction of lncRNA regulate phosphatidylinositol-3-kinase (PI3K)/AKT/mamma- UCA1 with miR-7-5p, elevating the expression of epidermal lian target of rapamycin (mTOR) signaling pathway and their growth factor receptor (EGFR) in hypoxia-resistant GC cells downstream mediators [49]. ,e overexpressed lncRNA UCA1 [54]. Nonetheless, chronic hypoxia environment with a increased the expression levels of key molecules in the PI3K/ slight increment in the protein levels of hypoxia-inducible AKT/mTOR signaling pathway, including AKT serine/threo- factor-1alpha (HIF-1α) could reduce lncRNA UCA1 ex- nine kinase 3 (AKT3), phosphorylated mammalian target of pression [54]. Taken together, these findings demonstrated Journal of Oncology 5 Table 1: Summary of the studies that assessed the expression and regulatory roles of lncRNA UCA1 in human cell lines and tissues of GI cancer. Cancer type Study subject Cell line Finding/mechanistic response Reference EC109, EC9706, KYSE150, KYSE510, (i) LncRNA UCA1 was overexpressed and contributed to poor prognosis 90 ESCC patients who underwent surgery [37] and NE1 (ii) Silenced lncRNA UCA1 decreased cell proliferation, migration, and invasion (i) LncRNA UCA1 was overexpressed and contributed to poor prognosis 66 esophageal cancer patients underwent surgical (ii) Sox4 was identified as a direct target gene of lncRNA UCA1 and acted as a EC9706 and KYSE [38] resection ceRNA (iii) LncRNA UCA1 reduced miR-204 level (i) LncRNA UCA1 was overexpressed in EC tissues with advanced EC stages and was associated with poor prognosis 110 EC tissues and 60 paired of adjacent nontumorous EC1, EC109, EC9706, KYSE150, and (ii) Overexpressed lncRNA UCA1 promoted cell proliferation and metastasis [39] Esophageal tissues Het-1A (iii) LncRNA UCA1 promoted glycolysis by sequestering miR-203 to increase cancer HK2 levels, resulting in enhanced Warburg effect (i) LncRNA UCA1 lowly expressed in tumor tissue compared to the adjacent 106 newly diagnosed patients with primary cancer and nontumor tissue EC109 [40] previously untreated ESCC (ii) LncRNA UCA1 suppressed ESCC via inhibition of Wnt signaling pathway (iii) LncRNA UCA1 reduced C-myc and active β-catenin protein expression (i) LncRNA UCA1 expression was decreased in EC tissues and plasma exosomes 15 paired EC tissues and adjacent normal tissues of EC (ii) LncRNA UCA1 inhibited cell proliferation, invasion, migration, and colony EC18, KYSE140, and NEEC [41] patients formation as well as inhibited tumor growth in vivo (iii) Exosomal lncRNA UCA1 directly targeted miRNA-613 in EC cells (i) Overexpressed lncRNA UCA1 in both GC tissue and plasma of GC patients 20 plasma samples of patients and pair-matched plasma Five GC tissues and five pair-matched Gastric cancer (ii) Plasma lncRNA UCA1 provided higher diagnostic performance for the [42] samples noncancerous tissues detection of GC 6 Journal of Oncology Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference (i) Overexpressed lncRNA UCA1 in GC human tissue and GC cell lines SGC-7901, BGC-823, MKN-28, AGS, 112 patients diagnosed with GC (ii) High lncRNA UCA1 expression correlated with worse differentiation, tumor [43] and GES-1 size, invasion depth, and TNM stage (i) Elevated lncRNA UCA1 in tumor tissues of GC patients Chinese patients BGC-823 and SGC-7901 (ii) LncRNA UCA1 promoted metastasis by sponging miR-203, resulting in ZEB [44] overexpression (i) LncRNA UCA1 expression was higher in GC compared to paracancerous Ten GC and ten paracancerous normal tissues from the MGC-803, SGC-7901, BGC-823, tissues [45] patients in China AGS, MKN-45, and GES-1. (ii) SATB1 and lncRNA UCA1 competitively bound to miR-495-3p that acts as a ceRNA and reduced its expression (i) Overexpressed lncRNA UCA1 in GC human tissue and GC cell lines AGS, MKN-28, SGC-7901, MKN-45, 62 GC patients who underwent surgical resection (ii) LncRNA UCA1 repressed miR-590-3p, leading to increased CREB1 [46] and GES-1 expression (i) Overexpressed lncRNA UCA1 in GC human tissue compared to adjacent noncancerous tissues 40 primary GC tissues and corresponding adjacent AGS, SGC-7901, BGC-823, MGC- (ii) LncRNA UCA1 repressed miR-26a/b, miR-193a, and miR-214 expression [47] nontumorous gastric tissue samples 803, and SNU-1 through direct interaction (iii) LncRNA UCA1 upregulated pdl1 (i) Overexpressed lncRNA UCA1 in GC human tissue compared to adjacent 37 paired GC tissues and corresponding adjacent normal HGC27, MGC803, NCI-N87, BGC- normal tissues [48] tissues 823, SGC7901, and GES-1 (ii) TGFb1-induced lncRNA UCA1 elevation and acceleration of EMT (i) ,e overexpression of UCA1 in GC was higher in GC tissue than adjacent Gastric cancer MKN-28, SGC-7901, MGC-803, noncancerous tissues, and it is correlated with TNM stage and lymph node 102 gastric cancer patients who underwent surgery [49] BGC-823, MKN-45, and GES-1 metastases (ii) LncRNA UCA1 activated PI3K-Akt-mTOR signaling pathway (i) LncRNA UCA1 highly expressed in GC tissues than its matched nontumor tissues BGC-823, SGC-7901, AGS, MKN-45, 39 patients with GC (ii) SP1 induced lncRNA UCA1 [50] NCI-N87, and MKN-28 (iii) EZH2 and lncRNA UCA1 interaction activated AKT/GSK-3B/cyclin D1 axis (i) LncRNA UCA1 was highly expressed in GC tissues than its adjacent MGC-803, HGC-27, NCI-N87, and nontumor tissues 49 patients with GC [51] GES-1 (ii) LncRNA UCA1 promoted tumor metastasis by inducing GRK2 degradation, which activated the ERK-MMP9 signaling pathway SGC-7901, SGC-7901, SGC-7901/ (i) LncRNA UCA1 was one of the lncRNAs overexpressed in GC tissue 28 primary GC patients who had not received previous ADR, SGC-7901/DDP, and SGC- [52] chemotherapy or radiotherapy (ii) Multidrug resistance of GC by repressing miR-27b 7901/FU (i) LncRNA UCA1 was highly expressed in GC tissues than its adjacent nontumor tissues 53 pairs of GC tissues and adjacent normal tissues GES-1, SNU-5, AGS, and NCI-N87 (ii) Knockdown of lncRNA UCA1 increased sensitivity to cisplatin by inducing [53] cell apoptosis (iii) LncRNA UCA1 reduced miR-513a-3p and elevated CYP1B1 (i) LncRNA UCA1 promoted the migration of hypoxia-resistant GC cells via — MGC-803 and BGC-823 [54] miR-7-5p/EGFR axis Journal of Oncology 7 Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference (i) HBx induced lncRNA UCA1 expression in hepatocytes (ii) LncRNA UCA1 reduced p27kip1 expression and increased EZH2 expression 60 paired tumorous and adjacent nontumorous liver LO2 cells and HBx-expressing via histone methylation on p27kip1 promoter region [55] tissues obtained immediately after surgical resection hepatoma cells (iii) LncRNA UCA1 induced CDK2 expression without altering CDK4 and CDK6 (i) LncRNA UCA1 highly expressed in 79 patients out of 88 HCC patients 88 HCC patients HepG2 and Huh7 [56] (ii) TGF-β1 induced the expression of lncRNA UCA1 and HXK2 (i) Overexpressed lncRNA UCA1 was detected in HCC tissues compared to healthy tissues (ii) miR-124 repressed ROCK1 66 newly diagnosed HCC patients SNU-398 and SNU-449 [57] (iii) ROCK1 reduced lncRNA UCA1 expression (iv) HBV and HCV infections did not affect the expression of lncRNA UCA1 and miR-124 (i) Overexpressed SND1 in HCC tissues than normal tissues 50 HCC patients from online data sets HEK 293t and HepG2 (ii) SND1 induced lncRNA UCA1 expression through the interaction of SND1 [58] with MYB Hepatobiliary (i) Arsenic stress induced lncRNA UCA1 cancer (ii) LncRNA UCA1 promoted protective roles of arsenic-induced cell death by blocking autophagic flux — HepG2 [59] (iii) LncRNA UCA1 protected HCC cells against arsenic stress by repressing miR-184 and elevating OSGIN1 that activated mTOR/p70S6K autophagy inhibition pathway HCCC-9810, RBE, QBC939, Huh-28, (i) LncRNA UCA1 was overexpressed in CCA tissues and cell lines 68 CCA patients HuCCT1, KMBC, CCLP-1, and (ii) LncRNA UCA1 inhibited apoptosis through Bcl-2/caspase-3 pathway [60] HIBEC (iii) Activated AKT/GSK-3β axis elevated CCND1 expression (i) LncRNA UCA1 was highly expressed lncRNA in CCA compared with LIPF155C, CCLP1, QBC939, huh28, paracarcinoma tissues 22 CCA patients receiving surgical resection [61] and HIBEC (ii) Regulation of miR-122/CLIC1 and activation of ERK/MAPK signaling pathway (i) High expression of lncRNA UCA1 was associated with tumor size, lymph 45 GBC tissues and neighboring noncancerous tissues node metastasis, TNM stage, and short survival time in GBC patients NOZ and GBC-SD [62] from patients who underwent liver resection (ii) Recruitment of EZH2 to the promoter of p21 and E-cadherin (iii) Epigenetically suppressed p21 and E-cadherin expression 128 PC patients received operation as initial systemic Panc-1, Bxpc-3, Capan-1,SW-1990, (i) LncRNA UCA1 overexpressed in PC tissue and cell lines [63] treatment and HPDE6C-7 (ii) LncRNA UCA1 suppressed p27 protein SW1990, BxPC-3, MiaPaCa-2, (iii) Highly expressed lncRNA UCA1 in PC tissues and cell lines 50 PC patients [64] PANC-1, CAPAN-1, and HPDE (iv) LncRNA UCA1 sponged miR135a (i) Out of 19 lncRNAs, lncRNA UCA1 was one of the overexpressed lncRNAs in HPC-Y5, PANC-1, SW1990, and 36 PC patients underwent surgical resection PC tissues [65] AsPC-1 (ii) LncRNA UCA1 repressed miR-96, resulting in increased FOXO3 expression Pancreatic (i) Higher mRNA levels of lncRNA UCA1 in PC tissues than normal pancreatic cancer Analysis of mRNA levels of lncRNA UCA1 in PC patients BxPC-3, SW1990, PaTu8988, and tissues and correlated with poor prognosis [66] from BADEA and TCGA databases PANC-1 (ii) LncRNA UCA1 promoted cell migration and invasion via Hippo signaling pathway (i) LncRNA UCA1 was highly expressed in PDAC tumor specimens than normal tissue Analysis of lncRNA UCA1 mRNA levels from TCGA PaTu8902, Mpanc96, HEK293T, and (ii) LncRNA UCA1 acted as a ceRNA to increase the expression of KRAS via [67] database in PDAC tumor specimens and normal H6C7 sponging miR-590-3p (iii) KRAS promoted lncRNA UCA1 expression. 8 Journal of Oncology Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference CaCO-2, SW480, HCT116, LoVo, and (i) Overexpressed lncRNA UCA1 promoted cell proliferation, apoptosis, and 80 CRC patients [68] CCC-HIE-2 cell cycle distribution Two CRC cohorts, including 90 and 119 human primary (i) Induced 5-FU resistance HEK-293T, HCT8, HCT116, HT29, CRC tissues and their paired adjacent noncancerous (ii) Inhibition of miR-204-5p and upregulated its target genes (e.g., bcl2, rab22a, [69] LoVo, and SW480 tissues, respectively and creb1) (i) Overexpressed lncRNA UCA1 in CRC tissues and cell lines NCM460, SW620, HT29, CACO2, (ii) LncRNA UCA1 repressed miR-28-5p level, which subsequently increased 60 CRC patients [70] SW480, and HCT116 HOXB3 axis (iii) LncRNA UCA1 elevated MMP2 and MMP9 (i) Overexpressed lncRNA UCA1 in CRC cell lines CCD-18Co, HIEC-6, SW620, and (ii) LncRNA UCA1 sponged miR-185-5p, leading to elevation of WNT1 and — [71] HT29 WISP2 that activated WISP2/b-catenin signaling pathway, which affected autophagy and survival of CRC (i) Overexpressed lncRNA UCA1 in CRC cell lines SW480, SW620, HT-29, CCD-18Co, — (ii) LncRNA UCA1 elevated the expression of MAPK14 to activate [72] and HIEC-6 MAPKAPK2/HSP27 signaling pathway (i) Overexpressed lncRNA UCA1 in CRC cell lines (ii) CAFs induced lncRNA UCA1 to increase the expression of mTOR Colorectal — SW480 and NF [73] (iii) LncRNA UCA1/mTOR axis repressed p27 and miR-143 and significantly cancer elevated cyclin D1 and KRAS expression (i) LncRNA UCA1 significantly expressed higher in CRC tissue after chemoradiotherapy Tissue from 32 CRC patients collected immediately after HCT116, CCL244, SW480, LoVo, and (ii) Downregulation of LncRNA UCA1 enhanced radiotherapy sensitivity [74] surgical resection FHC (iii) LncRNA UCA1 inhibited EMT by reducing MMP2, MMP9, ZEB1, and vimentin (i) 5-fluorouracil resistance of CRC was associated with lncRNA UCA1 25 CRC patients with 5-fluorouracil resistance and 25 abundance that promoted autophagy and inhibited apoptosis SW480, SW620, and 293T [75] CRC patients with 5-fluorouracil sensitivity (ii) LncRNA UCA1 sponged miR-23b-3p and consequently elevated ZNF281 expression (i) LncRNA UCA1 levels upregulated in cetuximab-resistant cells and their exosomes (ii) Exosomal lncRNA UCA1 was detectable and stable in the serum of CRC patients 53 CRC patients treated with cetuximab Caco2-CR and Caco2-CS [76] (ii) Exosomes originated from cetuximab-resistant cells could alter lncRNA UCA1 expression (iv) LncRNA UCA1 can be transferred from resistant cells to sensitive cells through exosomes Journal of Oncology 9 ROCK1 miR-204 sox4 miR-122 clic1 TGFβ1 snail2 zeb2 EMT miR-203 miR-135a HIF-1α Chromatin kras creb1 miR-495-3p satb1 miR-590-3p modification ceRNA/ HBx miRNA sponge miR-96 foxo3 miR-28-5p hoxb3 SND1 pdl1 miR-193a mapk14 miR-185-5p wnt1 wisp2 MYB LncRNA UCA1 pdl1 miR-214 fgfr1 miR-216b CAFs miR-27b Chemoresistance rab22a bcl2 SP1 miR-204-5p creb1 SATB1 miR-7-5p egfr HXK2 caspase-3 KRAS ZNF-281 miR-23b-3p miR-531a-3p CYP1B1 HXK2 miR-203 Upregulate/promote Downregulate Figure 2: Overview of the upstream and downstream regulation of lncRNA UCA1 on miRNAs, genes, and proteins in GI cancer. LncRNA UCA1 could be induced by TGF-β1, HIF-1α, HBx, SND1-MYB complexes, CAFs, SP1, SATB1, and KRAS proteins, while ROCK1 can repress its expression. In turn, it acts as a ceRNA and an mRNA sponge that can reduce miRNA expression, which further downregulate its mediating gene expression. Collectively, lncRNA UCA1 regulates this interaction network to promote cell proliferation, metastasis, and chemoresistance in different GI cancers. LncRNA UCA1 EZH2 miR-185-5p miR-216b CLIC1 AKT3 MOB1 EIF4E GRK2 Vimentin ZO-1 YAP Lats1 p-AKT3 Snail Cbl-c E-cadherin FGFR1 p27kip1 CDK2 ERK WNT1 MAPK14 p-mTOR MAPK YAP signaling AKT/GSK- p21 S6K pathway 3B/cyclin D1 ERK-MMP9 signaling ERK WISP2/ MAPKAPK2/ EMT E-cadherin signaling β-catenin pathway HSP27 signaling pathway Hippo signaling pathway pathway PI3K-Akt-mTOR pathway signaling pathway Cancer progression/Chemoresistance Upregulate/promote Downregulate Figure 3: ,e signaling pathway associated with lncRNA UCA1 in GI cancer. LncRNA UCA1 induces EMT by regulating EMT key proteins. It also promotes the activation of PI3K/Akt/mTOR signaling pathway, ERK/MMP9 signaling pathway, ERK signaling pathway, Hippo pathway, WISP2/β-catenin signaling pathway, and MAPKAPK2/HSP27 signaling pathway by regulating their key proteins. Additionally, lncRNA UCA1 also interacts with EZH2 to regulate protein expression. that the lncRNA UCA1 may facilitate GC development, 3.3. Hepatobiliary Cancer. Hepatobiliary cancer comprises progression, and chemoresistance via the interaction with tumors present in the liver, gallbladder, and bile duct different molecules, signaling pathways, and/or miRNAs. (cholangiocarcinoma). For instance, Wang et al. showed that Cancer progression Chemoresistance 10 Journal of Oncology contributed to As-induced autophagic flux blockage through lncRNA UCA1 was highly expressed in HCC and positively correlated with postoperative survival and tumor, node, and activating mTOR/ribosomal protein S6 kinase beta-1 (p70S6K) cascade and therefore resulting in compromised cell death [59]. metastasis (TNM) stage [78]. In addition, the result also showed that lncRNA UCA1 regulated fibroblast growth Nonetheless, this finding did not directly conclude the rela- factor receptor 1 (FGFR1)/ERK signaling pathway through tionship of lncRNA UCA1 with HCC progression. However, sponging miR-216b that led to downregulation of the mRNA the arsenic stress might resemble anticytotoxicity effects as levels of miR-216b. In contrast, upregulation was detected arsenic induces cell death. ,erefore, future studies should be for fgfr1 gene to activate the ERK signaling pathway [78]. conducted in order to relate the effects of lncRNA UCA1/ One of the known risk factors for HCC is hepatitis virus OSGIN1/mTOR/p70S6K with HCC progression. On the other hand, overexpressed lncRNA UCA1 in infection [79]. Interestingly, hepatitis B virus (HBV) can induce lncRNA UCA1 in HCC cells via their produced X protein cholangiocarcinoma (CCA) showed that it could act as an independent prognostic factor in CCA patients [60]. Similar (HBx) [55]. LncRNA UCA1 also significantly reduced p27kip1 expression along with the increased expression of EZH2 via to the finding reported by Wang et al. in GC, Xu et al. also found that enhanced CCA cell proliferation was via the histone methylation on p27kip1 promoter region [55]. In addition, ectopically expressed lncRNA UCA1 induced the activation of AKT/GSK-3β axis that led to upregulation of expression of cyclin-dependent kinase-2 (CDK2) but not for cyclin D1 (CCND1) expression [50, 60]. ,e apoptosis in- CDK4 and CDK6 where CDK2 regulated cell cycle and ap- hibition in highly lncRNA UCA1-expressed CCA cells might optosis, and its activity was regulated by CDK inhibitors (e.g., be partly due to B-cell lymphoma 2 (Bcl-2)/caspase-3 p21 and p27) [55]. However, only p27 expression was sup- pathway [60]. pressed in overexpressed HBx and lncRNA UCA1 HCC cells LncRNA UCA1 has also been reported to play an im- portant role in CCA metastasis through regulating miR-122/ [55]. ,erefore, this finding suggested that the regulating effects of lncRNA UCA1 are protein-specific despite originating from chloride intracellular channel 1 (CLIC1). For instance, both lncRNA UCA1 and CLIC1 were elevated, while miR-122 was the same upstream mediators. Apart from lncRNA UCA1, TGF-β1 and HXK2 were also reduced in bile duct carcinoma [61]. Also, both lncRNA UCA1 and CLIC1 promoted the phosphorylation of ERK found to be overexpressed in HCC patients [56]. Hu et al. suggested that TGF-β1 promoted HCC cell growth through and mitogen-activated protein kinase (MAPK), activating the induction of energy metabolism and subsequently ERK/MAPK signaling pathway to promote cancer cell promoted lncRNA UCA1 expression and its downstream metastasis [61]. regulator HXK2, an isozyme that involves in glycolysis [56]. Apart from HCC and CCA, lncRNA UCA1 is also over- Most studies have reported that lncRNA UCA1 is prone to expressed in gallbladder cancer (GBC) [62]. ,e overexpressed regulate miRNA expression, but Zhao et al. revealed that lncRNA UCA1 regulated tumor progression through the re- cruitment of EZH2 to the promoter of both tumor suppressor miR-124, a tumor suppressor mRNA, reduced rho-associ- ated protein kinase 1 (ROCK1) to suppress lncRNA UCA1 p21 and E-cadherin that resulted in their suppressed expression [62]. ,is observation is opposed to what discovered in HCC expression, leading to the inhibition of HCC cell prolifer- ation, migration, and invasion [57]. ,ey further discovered by Hu et al. for p21, which could be probably explained by that the expression of both lncRNA UCA1 and miR-124 was different cancer types used. not affected by HBV and HCV infections [57]. ,is finding, In short, these findings revealed the association of however, could be correct if lncRNA UCA1 is the down- lncRNA UCA1 in tumor progression, invasion, and me- stream target protein of miR-124 or incorrect if miRNA and tastasis of hepatobiliary cancer by regulating downstream lncRNA UCA1 are negatively regulated in which miRNAs molecules or be regulated by upstream mediators. usually downregulated when lncRNA UCA1 is overex- pressed as in most cancer types reported. 3.4. Pancreatic Cancer. Pancreatic cancer (PC) is the fourth Furthermore, staphylococcal nuclease and tudor domain leading cause of cancer-related deaths worldwide [80, 81]. containing 1 (SND1) can induce the expression of lncRNA According to Chen et al., lncRNA UCA1 overexpression was UCA1 through its interaction with myeloblastosis proto- detected in the tissues of 128 pancreatic cancer patients oncogene (MYB), a transcriptional activator, by forming SND1-MYB complex [58]. Meanwhile, SND1 itself acts as an compared to adjacent nontumor tissues [63]. Moreover, lncRNA UCA1 silencing inhibited cell proliferation and in- antiapoptotic factor in HCC [58]. Again, this finding sup- ported the previous hypothesis that lncRNA UCA1 ex- duced apoptosis and cell cycle arrest in PC cells [63]. ,ey also found the possible association of lncRNA UCA1 with the pression can be induced by another gene or protein. Meanwhile, an in vitro study involving HCC cells showed inhibition of p27 in their previous study on PC [63]. In ad- dition, lncRNA UCA1 was shown to regulate growth and that lncRNA UCA1 was substantially induced by arsenic (As) at metastasis by sponging miR-135a in PC [64]. Apart from the 10 μM/L with > 4-fold increase, denoting a protective role interaction with miR-135a, lncRNA UCA1 also inhibited miR- against As-induced cell death [59]. By using RNA-Seq assay, 96, a tumor suppressor mRNA, resulting in the upregulation of oxidative stress induced growth inhibitor 1 (OSGIN1) was forkhead box O-3 (FOXO3) to promote tumor progression uncovered to be the most responsive downstream target of [65]. lncRNA UCA1, and miR-184 acted as an intermediate for the regulation of lncRNA UCA1 on OSGIN1 expression through In PC cells, lncRNA UCA1 demonstrated to promote cell migration and invasion through Hippo pathway by ceRNA mechanism [59]. ,e lncRNA UCA1/OSGIN1 signaling Journal of Oncology 11 and drug resistance, while CREB1 transcription factor involves interacting with key proteins, such as Mps one binder kinase activator (MOB1), large tumor suppressor kinase 1 (Lats1), in CRC tumorigenesis [69, 83]. In addition to miR-204-5p, creb1 is also a target gene of miR-590-3p [46]. phosphorylated-Lats1, and Yes-associated protein (YAP) [66]. LncRNA UCA1 bound to MOB1, Lats1, and YAP to Similarly, lncRNA UCA1 also inhibited miR-28-5p ac- form three shielding composites, retaining YAP activation tivity to cause the overexpression of Homeobox B3 and leading to YAP translocation into the nucleus to induce (HOXB3), promoting CRC cell proliferation and migration gene expression for cell proliferation and apoptosis and for [70]. Cui et al. revealed that both lncRNA UCA1 silencing lncRNA UCA1 expression itself [66]. Moreover, lncRNA and elevation of miR-28-5p expression reduced the protein UCA1 also interacted with MOB1, Lats1, and YAP to form levels of MMP2 and MMP9 that play a crucial role in cancer ribonucleoprotein complex that could be another reason in cell metastasis [70]. regulating gene expression. In addition, upregulation of Interestingly, lncRNA UCA1 also has an miRNA sponging activity in CRC. For instance, it sponged miR-185- MMP (e.g., MMP14, MMP2, and MMP9) proteins were also detected in lncRNA UCA1-overexpressed PC cells, sug- 5p and led to overexpressed Wnt family member 1 (WNT1) and WNT1-inducible-signaling pathway protein 2 (WISP2); gesting the role of lncRNA UCA1 in invasion and migration [66]. ,is study indicated that lncRNA UCA1 could interact both activating WISP2/β-catenin signaling pathway to with key proteins and protein complexes by binding to their regulate autophagy and survival of CRC [71]. Apart from promoter region to enhance PC cell progression. wnt1 and wisp2, mapk14 is also a target gene of miR-185-5p, In pancreatic ductal adenocarcinoma (PDAC), lncRNA where upregulation of mapk14 activated mitogen-activated UCA1 regulated miR-590-3p to increase the expression of protein kinase-activated protein kinase 2 (MAPKAPK2)/ oncogenic Kirsten rat sarcoma viral oncogene homolog heat-shock protein 27 (HSP27) signaling pathway to pro- mote invasion, migration, and EMT [72]. (KRAS) protein, and KRAS itself can promote lncRNA UCA1 expression [67]. ,is discovery showed that lncRNA ,e interplay of CRC tumor microenvironment on the expression of lncRNA UCA1 has also been studied. Jahangiri UCA1 and its downstream protein could regulate each other. Previously, Gu et al. reported that lncRNA UCA1 was as- et al. demonstrated that cancer-associated fibroblasts (CAFs) activated lncRNA UCA1 to induce mTOR overexpression [73]. sociated with miR-590-3p in GC cells via the target gene of miR-590-3p and creb1 [46]. Interestingly, Liu et al. newly ,e active lncRNA UCA1/mTOR axis subsequently reduced discovered that kras is another target gene of miR-590-3p in the expression of tumor suppressor p27 and miR-143 while PDAC [67]. ,erefore, further studies could be conducted to significantly increased cyclin D1 and KRAS expression [73]. identify miRNA target genes associated with lncRNA UCA1 Nonetheless, they further discovered that mTOR can regulate to enhance the understanding of the exact mechanism in miR-143, but whether lncRNA UCA1 could directly regulate regulating PDAC progression. the expression of miR-143 is unknown. Interestingly, it was discovered that the expression of Interesting observation by using human PDAC PANC-1 cells showed the potential of ceRNA networks, consisting of lncRNA UCA1 was significantly higher in four CRC human tissues and CCL244 CRC cells, but no significant difference was lncRNAs, circRNAs, and mRNAs, to be involved in autophagy suppression of PDAC caused by chloroquine diphosphate [82]. observed in HCT-116 CRC cells after chemoradiotherapy [74]. By using microarrays, numerous ceRNAs exhibited target as- ,is observation may indicate that lncRNA UCA1 plays a sociations with miR-663a-5p and miR-154-3p, and negative regulatory role in CRC radioresistance. Nevertheless, when associations with the expression of the targeted miRNAs under lncRNA UCA1 was silenced, it enhanced the radiotherapy the same changes in the autophagic level were determined [82]. sensitivity of CRC cells via X-ray irradiation-induced apoptosis ,e study also demonstrated that AC024560.2 competitively and prolonged G2/M cell cycle [74]. Yang et al. further showed binds to miR-663a-5p and thus regulates the autophagic level of that low level of lncRNA UCA1 inhibited EMT induction by PDAC cells by inhibiting the expression of this miRNA [82]. significantly suppressing the expression of EMT-regulating proteins, such as MMP2, MMP9, ZEB1, and vimentin [74]. In ,is shows that the ceRNAs including lncRNA could be a potential molecular target in diagnosis and treatment of PC. addition, the regulation of lncRNA UCA1 in CRC chemo- resistance is also facilitated by autophagy. For instance, it was To sum up, lncRNA UCA1 plays a significant role in PC progression that could be a novel independent predictor of shown to promote 5-fluorouracil resistance in CRC cells by the poor survival of PC patients, as well as a promising facilitating autophagy mediated by repressed miR-23b-3p and biomarker in cancer therapy. elevated zinc finger protein 281 (ZNF281) [75]. Similarly, lncRNA UCA1 also mediated autophagy to protect BC against rapamycin by inducing miR-582-5p-regulated autophagy-re- 3.5. Colorectal Cancer. Highly expressed lncRNA UCA1 is also lated protein 7 (ATG7) [84]. reported in colorectal cancer (CRC) cells and contributed to Meanwhile, Yang et al. illustrated that exosomal lncRNA tumorigenic activity [68]. For instance, overexpressed lncRNA UCA1 could be a promising biomarker for effective diag- UCA1 reduced miR-204-5p expression in CRC cells to enhance nosis and targeted therapy as exosomal lncRNA UCA1 can the expression of miR-204-5p target proteins, such as BCL2, ras- be assayed in a noninvasive manner and found to be rela- related protein (RAB22A), and CREB1 [69]. Elevated expres- tively abundant and stable in the serum of CRC patients [76]. sion of BCL2 and RAB22A can promote CRC cell proliferation To note, exosomes originated from cetuximab-resistance cell 12 Journal of Oncology against various cancers, including GI cancer [88–90]. In con- can alter the expression of lncRNA UCA1 and enhance resistance to cetuximab in CRC cells in view of the fact that clusion, lncRNA UCA1 has been identified as a novel and potential molecular target for GI cancer in the last decade based lncRNA UCA1 can transmit cetuximab resistance to sen- sitive cells [76]. Given this circumstance, exosomal lncRNA on its potent regulatory roles in cancer progression and che- UCA1 indeed has a great potential to be used as an evalu- moresistance. However, to enhance its translation possibility to ation factor for predicting cetuximab chemoresistance in clinical trials, more preclinical studies using both in vitro and in CRC patients. vivo models should be conducted to further explore the key In summary, lncRNA UCA1 participated significantly in mechanism of actions underlying its regulatory roles. Also, the CRC progression, invasion, migration, metastasis, lncRNA UCA1, particularly enriched in exosomes, can be a radioresistance, and chemoresistance. ,erefore, lncRNA potential diagnostic and prognostic biomarker compared to UCA1 can be a promising molecular target to combat CRC other molecular targets due to its high stability and availability in various human body fluids, including urine for BC [13], in chemotherapy, as well as in diagnostic and prognostic purpose of CRC patients. serum for HCC [91], and plasma sample in early GC [42], as well as its possible simplicity of extraction and diagnostic testing procedures. 4. Conclusion ,is review has provided an insight into the regulatory roles Data Availability and patterns of lncRNA UCA1 in GI cancer progression and chemoresistance, as well as its underlying mechanisms and ,e data supporting this manuscript are extracted from the interaction with key molecules involved, which may serve as previously reported studies and data sets, which have all a novel and highly potential molecular target for GI cancer been cited. therapy. It has discovered that multiple preclinical and clinical studies supporting the oncogenic role of lncRNA Conflicts of Interest UCA1 in GI cancer. In addition, the potential of lncRNA ,e authors declare that they have no conflicts of interest. UCA1 to be used as a prognostic marker has also been reported in several studies, where its expression correlates with the TNM stage of GI cancer [85]. Based on the findings Authors’ Contributions in this review, it was revealed that basic overexpression of lncRNA UCA1 has a positive implication in initiation, All authors contributed equally to this paper. proliferation, invasion, migration, and chemoresistance of GI cancer, although contradictory findings claim that it also Acknowledgments has anticancer activity, via the interactions with upstream and/or downstream molecules, signaling pathways, or bio- ,is work was supported by the Fundamental Research Grant Scheme (project no. FRGS/1/2019/SKK10/MAHSA/ logical processes. ,e regulatory roles of lncRNA UCA1 in 03/1) and MAHSA University research grant (project no. GI cancer progression are relatively observed more in GC RP165-05/19). followed by CRC. Comparatively, the regulation of che- moresistance by lncRNA UCA1 has so far discovered only in GC and CRC [16]. In general, lncRNA UCA1 interacts with References miRNAs, leading to the reduction of its target gene ex- [1] J. C. 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Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns, Mechanisms, and Interactions

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Copyright © 2021 Suaidah Ramli 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.
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Abstract

Hindawi Journal of Oncology Volume 2021, Article ID 5519720, 15 pages https://doi.org/10.1155/2021/5519720 Review Article Long Noncoding RNA UCA1 in Gastrointestinal Cancers: Molecular Regulatory Roles and Patterns, Mechanisms, and Interactions 1 1 2 3,4 Suaidah Ramli , Maw Shin Sim , Rhanye M. Guad , Subash C. B Gopinath , 5 6 6 Vetriselvan Subramaniyan , Shivkanya Fuloria , Neeraj K. Fuloria , 7 8 9 Ker Woon Choy , Sohel Rana , and Yuan Seng Wu Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Malaysia Department of Biomedical Science and &erapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia School of Bioprocess Engineering, Universiti Malaysia Perlis, Arau 02600, Perlis, Malaysia Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar 01000, Perlis, Malaysia Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor 42610, Malaysia Faculty of Pharmacy, AIMST University, Bedong, Kedah 08100, Malaysia Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Shah Alam, Sungai Buloh 47000, Selangor, Malaysia Department of Pharmacy, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore-7400, Bangladesh Department of Biochemistry, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor 42610, Malaysia Correspondence should be addressed to Yuan Seng Wu; sengwu_21@yahoo.com Received 29 January 2021; Revised 15 March 2021; Accepted 26 March 2021; Published 12 April 2021 Academic Editor: Dan Zhao Copyright © 2021 Suaidah Ramli et al. ,is 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. ,e rising trend of gastrointestinal (GI) cancer has become a global burden due to its aggressive nature and poor prognosis. Long noncoding RNAs (lncRNAs) have recently been reported to be overexpressed in different GI cancers and may contribute to cancer progression and chemoresistance. ,ey are featured with more than 200 nucleotides, commonly polyadenylated, and lacking an open reading frame. LncRNAs, particularly urothelial carcinoma-associated 1 (UCA1), are oncogenes involved in regulating cancer progression, such as cell proliferation, invasion, migration, and chemoresistance, particularly in GI cancer. ,is review was aimed to present an updated focus on the molecular regulatory roles and patterns of lncRNA UCA1 in progression and che- moresistance of different GI cancers, as well as deciphering the underlying mechanisms and its interactions with key molecules involved, together with a brief presentation on its diagnostic and prognostic values. ,e regulatory roles of lncRNA UCA1 are implicated in esophageal cancer, gastric cancer, pancreatic cancer, hepatobiliary cancer, and colorectal cancer, where they shared similar molecular mechanisms in regulating cancer phenotypes and chemoresistance. Comparatively, gastric cancer is the most intensively studied type in GI cancer. LncRNA UCA1 is implicated in biological roles of different GI cancers via interactions with various molecules, particularly microRNAs, and signaling pathways. In conclusion, lncRNA UCA1 is a potential molecular target for GI cancer, which may lead to the development of a novel chemotherapeutic agent. Hence, it also acts as a potential diagnostic and prognostic marker for GI cancer patients. 2 Journal of Oncology chemoresistance in BLS-211 BC cells [13]. In the last decade, 1. Introduction the regulatory roles of lncRNAs have been intensively in- Gastrointestinal (GI) cancer has become one of the major vestigated in which most studies have suggested that the challenges in the health sector in recent decades. GI cancer is mechanistic pathways underlying the regulatory roles of a group of cancers that affect the GI tract, such as esophagus, lncRNA UCA1. In this context, its interaction with the key stomach, gallbladder, liver, biliary tract, small intestine, and genes or proteins is the key causative factor that leads to the large intestine [1, 2]. In 2018, GI cancer contributed 26% development of GI cancer. among all cancer cases and 35% of cancer-causing death ,erefore, this review aims to provide a detailed insight into worldwide [3]. ,ere are five major GI cancers, namely, the regulatory roles of lncRNA UCA1 in GI cancer progression gastric cancer (GC), hepatobiliary cancer, esophageal cancer and chemoresistance, as evidenced in preclinical and clinical (EC), pancreatic cancer (PC), and colorectal cancer (CRC), studies. In addition, it also discusses various molecular accounting for approximately 1 million, 840,000, 570,000, mechanisms underlie and the key molecules involved, intending 460,000, and 1.7 million new cases were reported in 2018, to present its potential as a novel molecular target, as well as a respectively [4]. Comparatively, EC, GC, and liver cancer diagnostic and prognostic marker for GI cancer. (LC) are predominant in Asian population, whereas CRC shows more incidence in Europe and North America [3]. 2. LncRNA UCA1 Apart from that, GI cancer shows a reduced 5-year survival rate and a poor prognosis at the late stage of cancer [5]. Over the past few years, there is a bloom of transcriptome Generally, several factors have been reported to be the studies associated with the advancement in RNA sequencing contributing risk factors for GI cancer, including tobacco technology, which enables the view of the complexity of smoking, alcohol consumption, diet, and obesity and in- eukaryotic gene expression [20]. ,is advanced technology fections, such as Helicobacter pylori in GC and hepatitis virus leads to the discovery of lncRNAs [21]. More than 98% of the in LC [3, 6, 7]. genomes transcribed into ncRNAs are categorized, either as With the recent advancement in RNA sequencing structural RNAs or regulatory RNAs, where lncRNA is technology transcriptome knowledge, there are increased classified under regulatory RNAs [22]. LncRNAs are dis- interests in long noncoding RNAs (lncRNAs) as they play covered as an important new player in cell differentiation an important role in tumorigenesis, particularly gene and development, as well as organogenesis and genomic regulation [8, 9]. LncRNA is characterized by possessing imprinting [23, 24]. Additionally, most lncRNAs, including more than 200 nucleotides that would not be translated lncRNA UCA1, are much like mRNAs where they are into protein [10]. It can be found in both nucleus and transcribed by RNA polymerase II with similar chromatin cytoplasm where the chromatin remodeling, transcrip- states to mRNAs, and they usually 5′capped, spliced, and tional regulation, and RNA processing take place in the polyadenylated [25, 26]. ,e biogenesis of lncRNA UCA1 is nucleus, while its interaction with mRNA and signaling illustrated in Figure 1. pathway occurs in the cytoplasm [11, 12]. One of the re- It has been reported that several lncRNAs participate in ported cancer-related lncRNAs is urothelial carcinoma- the special processing events, including DNA organization. associated 1 (UCA1) that was first discovered in 2006 as it In this event, genomic DNA is packed in the nucleus with a was found to be overexpressed in bladder cancer (BC) cells, special genomic organization, depending on both histone a cancer close to but not belonged to GI cancer [13]. It and chromatin modifications that are regulated by epige- belongs to human endogenous retrovirus H family and is netic complexes and affect the transcriptional activity located at 19p13.12 of the chromosomes positive-strand [27, 28]. For instance, lncRNA metastasis-associated lung with three exons and two introns [13]. To date, three adenocarcinoma transcript 1 (MALAT1) and lncRNA nu- lncRNA UCA1 isoforms produced by RNA splicing have clear enriched abundant transcript 1 (NEAT1) are localized been discovered, and each of them with different sizes, at the nuclear speckles and nuclear paraspeckles, respec- including 1.4, 2.2, and 2.7 kb [14, 15]. Among them, 1.4 kb tively, after processing at 3′ ends by RNA polymerase II to lncRNA UCA1 is the most assessed and abundant isoform, form tRNA-like small RNA products and mature lncRNAs while 2.2 kb isoform is relatively more participated in [25, 29, 30]. However, the exact DNA organization for chemoresistance [14]. For instance, Wang et al. showed lncRNA UCA1 remains to be confirmed. Functionally, that lncRNA UCA1 significantly associated with cancer lncRNAs are involved in chromatin and epigenetic modi- chemoresistance toward cisplatin, gemcitabine, 5-fluoro- fications [31, 32]. LncRNA UCA1 also acts as an miRNA uracil, tamoxifen, and imatinib. Interestingly, the che- decoy and miRNA sponge, which sequester miRNA intra- mosensitivity of these drugs was significantly increased cellularly and compete with other genes for miRNA binding, when lncRNA UCA1 was silenced [16]. leading to an increased level of miRNA target gene ex- Apart from these, lncRNA UCA1 has been detected to be pression [1, 33]. overexpressed in various cancers, particularly GI cancers, Furthermore, lncRNA has also shown to play an im- such as CRC, esophageal squamous cell carcinoma (ESCC), portant role in embryogenesis where it has been identified to hepatocellular carcinoma (HCC), and GC [17–19]. Among be upregulated after 28 weeks of gestational in the tissue of lncRNAs, lncRNA UCA1 has been demonstrated to have heart, urinary bladder, and uterus, but downregulation is significant regulatory roles in cancer progression, including detected in liver, kidney, lung, spleen, intestine, stomach, cell proliferation, invasion, migration and metastasis, and skin, and cervix. In adult tissues, lncRNA UCA1 expression Journal of Oncology 3 cell nucleus and myelocytomatosis proto-oncogene (C- is relatively conserved at a low expression level, except for heart, spleen, and placenta [34]. In short, the ideal ex- myc), which is a target protein of Wnt signaling pathway in regulating cell cycle. ,is action ultimately reduced cancer pression of lncRNA UCA1 is remarkably essential for cell growth and development, particularly in embryogenesis cell proliferation, migration, and invasion [40]. Similarly, stage. Zhu et al. also demonstrated that lncRNA UCA1 was lowly expressed in EC tissues and plasma exosomes, which is a lipid-bilayer extracellular vesicle used as a cargo system for 3. Molecular Regulatory Roles, Patterns, various molecules, including lncRNAs, for implicating in the Mechanisms, and Interactions of LncRNA pathogenesis of many diseases, including cancer, by regu- UCA1 in Different Gastrointestinal Cancers lating intercellular communication. ,ey specifically found that exosomal lncRNA UCA1 could act as a growth inhibitor It has been reported that high expression levels of lncRNA in EC as its overexpression inhibited cell proliferation, UCA1 are detected in GI cancer cells [35, 36]. ,us, lncRNAs migration, invasion, and colony formation significantly, as may play an important role for GI tumorigenesis. ,e well as tumor growth in vivo via direct targeting of high positive association of lncRNA UCA1 with the overall levels of miR-613 [41]. It also acts as a potent diagnostic survival of GI cancer patients was revealed in a meta-analysis biomarker for EC, with great sensitivity (86.7%) and spec- [35]. ,e pooled result of 14 studies indicated that poor ificity (70.2%) [41]. However, these findings need to be overall survival in patients with digestive malignancies was further assessed as there is increasing evidence showing that associated with lncRNA UCA1 overexpression [35]. Since lncRNA UCA1 acts as an oncogenic lncRNA instead of then, different studies were conducted to further discover having tumor-suppressing function. Taken together, further the association between GI cancer and lncRNA UCA1 as well molecular studies of lncRNA UCA1 should be conducted to as identify the possible mechanisms responsible for GI elucidate its associated molecular mechanisms of regulatory cancer progression. In this review, the expression pattern, roles in EC clearly. regulatory roles and patterns, mechanistic pathways, and interactions of key molecules that are associated with lncRNA UCA1 in GI cancer progression and chemo- 3.2. Gastric Cancer. GC is one of GI cancers that contribute resistance, including EC, GC, hepatobiliary cancer, PC, and to high mortality due to late diagnosis [3, 77]. Intriguingly, CRC, are summarized (Table 1). A brief insight of the po- Gao et al. suggested that lncRNA UCA1 could be a potential tential role of lncRNA UCA1 as a diagnostic and prognostic diagnostic and biomarker target in the early stage of GC, marker, wherever applicable in different GI cancers, is also owing to the fact that highly expressed lncRNA UCA1 can be presented. ,e interaction of lncRNA UCA1 that affects the easily found in the plasma of GC patients and therefore target gene expression of miRNAs and activation of pivotal provides simplicity for sample extraction [42]. Similarly, it signaling pathway are illustrated in Figures 2 and 3, has also been discovered that lncRNA UCA1 is overex- respectively. pressed in both GC tumor and cell lines [43]. Moreover, it was also reported to play a role in GC cell migration and invasion via the induction of epithelial-mesenchymal 3.1. Esophageal Cancer. In ESCC patients, the most pre- transition (EMT) by competitively binding to miR-203, dominant deadly types of EC, lncRNA UCA1 has been reported to be overexpressed and contributed to poor prognosis [37]. increasing the expression of its target protein, Zinc Finger E-Box Binding Homeobox 2 (ZEB2) [44]. Jiao et al. showed that lncRNA UCA1 was strongly associated with EC cell proliferation by functioning as a competing en- In addition to miR-203, lncRNA UCA1 also interacts with miR-495-3p, supporting the role of UCA1 acting as a dogenous RNA (ceRNA) to regulate the expression of Sry- related high-mobility group box 4 (Sox4), a target protein of ceRNA [45]. Sun et al. reported that lncRNA UCA1 ex- pression could be regulated by special AT-rich-binding lncRNA UCA1 [38]. Additionally, lncRNA UCA1 also can protein 1 (SATB1), which was involved in chromatin directly interact with miR-204 to reduce miR-204-mediated modification in both MKN-45 and BGC-823 GC cells [45]. Sox4 degradation; thus, Sox4 can exert its biological role as a However, lncRNA UCA1 only regulated the protein levels tumor-promoting protein to stimulate EC progression [38]. of SATB1 in MKN-45 GC cells but not in BGC-823 cells Apart from that, overexpressed lncRNA UCA1 could also [45]. ,us, further investigation is required to discover the promote cell proliferation and metastasis by enhancing aerobic glycolysis through Warburg effect [39]. ,ese happened when rationale for obtaining such findings. Similarly, lncRNA UCA1 has also found to regulate lncRNA UCA1 sequestered miR-203, which then increased the levels of hexokinase 2 (HXK2) [39]. miR-590-3p expression that results in the activation of cAMP-responsive element-binding protein 1 (CREB1), Despite several studies have reported a positive corre- lation between overexpressed lncRNA UCA1 and tumor which is an oncogenic protein [46]. In addition, it plays a role in suppressing the immune system of GC cells by progression; however, contradictory findings were reported. elevating the expression of programmed death-1 ligand-1 For instance, Wang et al. discovered that overexpression of (PDL1) via sponging miR-193a and miR-214 [47]. In lncRNA UCA1 suppressed ESCC cell growth via the inhi- addition, Wang et al. also reported that lncRNA UCA1 bition of Wnt signaling pathway by suppressing β-catenin could sponge other miRNAs, for instance, miR-26a and activity [40]. ,ey claimed that lncRNA UCA1 could reduce miR-26b, thereby reducing their expression levels [47]. the expression of active β-catenin protein expression in the 4 Journal of Oncology rapamycin (p-mTOR), and ribosomal protein S6 kinase (S6K), RNA polymerase II while reducing the eukaryotic translation initiation factor 4E (EIF4E) protein levels in GC cells [49]. Consequently, the regulation of these proteins promoted GC cell growth and DNA proliferation [49]. ,is finding showed that lncRNA UCA1 could regulate multiple proteins involved in a signaling pathway. Transcription On the other hand, Wang et al. reported that specificity protein 1 (SP1) promoted the expression of lncRNA UCA1 in GC cells by binding to the core promoter of UCA1 [50]. ,e expressed lncRNA UCA1 was then activated AKT/GSK- RNA polymerase II 3 B/cyclin D1 axis by interacting with enhancer of zeste homolog 2 (EZH2), a histone methyltransferase [50]. Meanwhile, the interaction of lncRNA UCA1 enhanced EZH2 expression, which subsequently elevated the expres- sion of cyclin D1 to promote cell cycle [50]. ,ese findings Post-transcriptional supported the previous hypothesis that the association of processing lncRNA UCA1 in regulating other genes via epigenetic modification, which is histone modification in this case. ,e AAAAAA association of lncRNA UCA1 with AKT/GSK-3B/cyclin D1 was also identified in HCC [60]. Mature lncRNA UCAl In addition to EMT, lncRNA UCA1 can induce GC Figure 1: Biogenesis of lncRNA UCA1. LncRNA UCA1 is pro- metastasis by regulating G protein-coupled receptor kinase 2 duced by transcriptional process mediated by RNA polymerase II (GRK2) degradation and Casitas B-lineage Lymphoma (Cbl- from DNA template. It then undergoes special posttranscriptional c)-mediated ubiquitination, resulting in the activation of processing events, including 5′-capping, splicing, polyadenylation, extracellular-signal-regulated kinase (ERK)/matrix metal- and chemical base modification, to become a mature form. loproteinase-9 (MMP-9) signaling pathway [51]. Wang et al. demonstrated that lncRNA UCA1 interacted with GRK2 and ,is finding indicated that lncRNA UCA1 could function led to the exposure of GRK2 ubiquitination sites toward Cbl- as an miRNA sponge to reduce miRNA expression in the c for its degradation [51]. Consequently, the degraded GRK2 cells, subsequently reducing its inhibitory effects on the activated ERK/MMP-9 signaling pathway, which increased target protein. On the other hand, reduced ki-67 protein MMP-9 protein levels, to promote cell membrane degra- levels and increased levels of cleaved poly [ADP-ribose] dation, facilitating cancer cell migration and invasion [51]. polymerase 1 (PARP1) and cleaved caspase 3 were ob- ,is finding showed that lncRNA UCA1 could regulate the served in GC cells after lncRNA UCA1 silencing [47]. level of another protein by direct binding for degradation. However, the exact mechanism of lncRNA UCA1 in LncRNA UCA1 also plays a prominent role in chemo- regulating ki-67, PARP1, and caspase 3 is unknown, and resistance via miRNA signaling. For instance, the silenced further confirmation is required, particularly in identi- lncRNA UCA1 could upregulate the mRNA levels of miR- fying miRNAs or proteins associated with the regulation 27b and lead to reduced IC of doxorubicin, cisplatin, and of lncRNA UCA1. 5-fluorouracil, as well as promoting doxorubicin-induced In addition, Zuo et al. demonstrated that the induction apoptosis in doxorubicin-resistance SGC-7901 GC cells [52]. of high lncRNA UCA1 expression in GC cells was mediated In other words, the reduction of lncRNA UCA1 expression by transforming growth factor β1 (TGF-β1) [48]. ,e could improve the chemosensitivity of chemotherapeutic overexpressed lncRNA UCA1 consequently promoted EMT agents, at least for doxorubicin, cisplatin, and 5-fluorouracil by regulating the expression levels of EMT-related proteins, in GC therapy. Correspondingly, Cheng et al. reported that such as E-cadherin, vimentin, snail, and zonula occludens-1 lncRNA UCA1 silencing enhanced GC chemosensitivity (ZO-1) [48]. For instance, the mRNA levels of epithelial cell toward cisplatin by regulating the expression of miR-513a- markers, such as E-cadherin and ZO-1, were reduced, while 3p and Cytochrome P450 1B1 (CYP1B1) [53]. an elevation was observed for mesenchymal cell markers, Chemoresistance is also affected by cancer microenvi- namely vimentin and snail [48]. ,is finding indicated that ronment, such as hypoxic microenvironment, that claims to apart from regulating other genes or proteins, lncRNA block the exposure of chemotherapeutic agents to cancer UCA1 also can be regulated by other genes or proteins. cells [54]. Yang et al. reported that GC cells could survive in Meanwhile, lncRNA UCA1 has also been reported to the hypoxic environment via the interaction of lncRNA regulate phosphatidylinositol-3-kinase (PI3K)/AKT/mamma- UCA1 with miR-7-5p, elevating the expression of epidermal lian target of rapamycin (mTOR) signaling pathway and their growth factor receptor (EGFR) in hypoxia-resistant GC cells downstream mediators [49]. ,e overexpressed lncRNA UCA1 [54]. Nonetheless, chronic hypoxia environment with a increased the expression levels of key molecules in the PI3K/ slight increment in the protein levels of hypoxia-inducible AKT/mTOR signaling pathway, including AKT serine/threo- factor-1alpha (HIF-1α) could reduce lncRNA UCA1 ex- nine kinase 3 (AKT3), phosphorylated mammalian target of pression [54]. Taken together, these findings demonstrated Journal of Oncology 5 Table 1: Summary of the studies that assessed the expression and regulatory roles of lncRNA UCA1 in human cell lines and tissues of GI cancer. Cancer type Study subject Cell line Finding/mechanistic response Reference EC109, EC9706, KYSE150, KYSE510, (i) LncRNA UCA1 was overexpressed and contributed to poor prognosis 90 ESCC patients who underwent surgery [37] and NE1 (ii) Silenced lncRNA UCA1 decreased cell proliferation, migration, and invasion (i) LncRNA UCA1 was overexpressed and contributed to poor prognosis 66 esophageal cancer patients underwent surgical (ii) Sox4 was identified as a direct target gene of lncRNA UCA1 and acted as a EC9706 and KYSE [38] resection ceRNA (iii) LncRNA UCA1 reduced miR-204 level (i) LncRNA UCA1 was overexpressed in EC tissues with advanced EC stages and was associated with poor prognosis 110 EC tissues and 60 paired of adjacent nontumorous EC1, EC109, EC9706, KYSE150, and (ii) Overexpressed lncRNA UCA1 promoted cell proliferation and metastasis [39] Esophageal tissues Het-1A (iii) LncRNA UCA1 promoted glycolysis by sequestering miR-203 to increase cancer HK2 levels, resulting in enhanced Warburg effect (i) LncRNA UCA1 lowly expressed in tumor tissue compared to the adjacent 106 newly diagnosed patients with primary cancer and nontumor tissue EC109 [40] previously untreated ESCC (ii) LncRNA UCA1 suppressed ESCC via inhibition of Wnt signaling pathway (iii) LncRNA UCA1 reduced C-myc and active β-catenin protein expression (i) LncRNA UCA1 expression was decreased in EC tissues and plasma exosomes 15 paired EC tissues and adjacent normal tissues of EC (ii) LncRNA UCA1 inhibited cell proliferation, invasion, migration, and colony EC18, KYSE140, and NEEC [41] patients formation as well as inhibited tumor growth in vivo (iii) Exosomal lncRNA UCA1 directly targeted miRNA-613 in EC cells (i) Overexpressed lncRNA UCA1 in both GC tissue and plasma of GC patients 20 plasma samples of patients and pair-matched plasma Five GC tissues and five pair-matched Gastric cancer (ii) Plasma lncRNA UCA1 provided higher diagnostic performance for the [42] samples noncancerous tissues detection of GC 6 Journal of Oncology Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference (i) Overexpressed lncRNA UCA1 in GC human tissue and GC cell lines SGC-7901, BGC-823, MKN-28, AGS, 112 patients diagnosed with GC (ii) High lncRNA UCA1 expression correlated with worse differentiation, tumor [43] and GES-1 size, invasion depth, and TNM stage (i) Elevated lncRNA UCA1 in tumor tissues of GC patients Chinese patients BGC-823 and SGC-7901 (ii) LncRNA UCA1 promoted metastasis by sponging miR-203, resulting in ZEB [44] overexpression (i) LncRNA UCA1 expression was higher in GC compared to paracancerous Ten GC and ten paracancerous normal tissues from the MGC-803, SGC-7901, BGC-823, tissues [45] patients in China AGS, MKN-45, and GES-1. (ii) SATB1 and lncRNA UCA1 competitively bound to miR-495-3p that acts as a ceRNA and reduced its expression (i) Overexpressed lncRNA UCA1 in GC human tissue and GC cell lines AGS, MKN-28, SGC-7901, MKN-45, 62 GC patients who underwent surgical resection (ii) LncRNA UCA1 repressed miR-590-3p, leading to increased CREB1 [46] and GES-1 expression (i) Overexpressed lncRNA UCA1 in GC human tissue compared to adjacent noncancerous tissues 40 primary GC tissues and corresponding adjacent AGS, SGC-7901, BGC-823, MGC- (ii) LncRNA UCA1 repressed miR-26a/b, miR-193a, and miR-214 expression [47] nontumorous gastric tissue samples 803, and SNU-1 through direct interaction (iii) LncRNA UCA1 upregulated pdl1 (i) Overexpressed lncRNA UCA1 in GC human tissue compared to adjacent 37 paired GC tissues and corresponding adjacent normal HGC27, MGC803, NCI-N87, BGC- normal tissues [48] tissues 823, SGC7901, and GES-1 (ii) TGFb1-induced lncRNA UCA1 elevation and acceleration of EMT (i) ,e overexpression of UCA1 in GC was higher in GC tissue than adjacent Gastric cancer MKN-28, SGC-7901, MGC-803, noncancerous tissues, and it is correlated with TNM stage and lymph node 102 gastric cancer patients who underwent surgery [49] BGC-823, MKN-45, and GES-1 metastases (ii) LncRNA UCA1 activated PI3K-Akt-mTOR signaling pathway (i) LncRNA UCA1 highly expressed in GC tissues than its matched nontumor tissues BGC-823, SGC-7901, AGS, MKN-45, 39 patients with GC (ii) SP1 induced lncRNA UCA1 [50] NCI-N87, and MKN-28 (iii) EZH2 and lncRNA UCA1 interaction activated AKT/GSK-3B/cyclin D1 axis (i) LncRNA UCA1 was highly expressed in GC tissues than its adjacent MGC-803, HGC-27, NCI-N87, and nontumor tissues 49 patients with GC [51] GES-1 (ii) LncRNA UCA1 promoted tumor metastasis by inducing GRK2 degradation, which activated the ERK-MMP9 signaling pathway SGC-7901, SGC-7901, SGC-7901/ (i) LncRNA UCA1 was one of the lncRNAs overexpressed in GC tissue 28 primary GC patients who had not received previous ADR, SGC-7901/DDP, and SGC- [52] chemotherapy or radiotherapy (ii) Multidrug resistance of GC by repressing miR-27b 7901/FU (i) LncRNA UCA1 was highly expressed in GC tissues than its adjacent nontumor tissues 53 pairs of GC tissues and adjacent normal tissues GES-1, SNU-5, AGS, and NCI-N87 (ii) Knockdown of lncRNA UCA1 increased sensitivity to cisplatin by inducing [53] cell apoptosis (iii) LncRNA UCA1 reduced miR-513a-3p and elevated CYP1B1 (i) LncRNA UCA1 promoted the migration of hypoxia-resistant GC cells via — MGC-803 and BGC-823 [54] miR-7-5p/EGFR axis Journal of Oncology 7 Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference (i) HBx induced lncRNA UCA1 expression in hepatocytes (ii) LncRNA UCA1 reduced p27kip1 expression and increased EZH2 expression 60 paired tumorous and adjacent nontumorous liver LO2 cells and HBx-expressing via histone methylation on p27kip1 promoter region [55] tissues obtained immediately after surgical resection hepatoma cells (iii) LncRNA UCA1 induced CDK2 expression without altering CDK4 and CDK6 (i) LncRNA UCA1 highly expressed in 79 patients out of 88 HCC patients 88 HCC patients HepG2 and Huh7 [56] (ii) TGF-β1 induced the expression of lncRNA UCA1 and HXK2 (i) Overexpressed lncRNA UCA1 was detected in HCC tissues compared to healthy tissues (ii) miR-124 repressed ROCK1 66 newly diagnosed HCC patients SNU-398 and SNU-449 [57] (iii) ROCK1 reduced lncRNA UCA1 expression (iv) HBV and HCV infections did not affect the expression of lncRNA UCA1 and miR-124 (i) Overexpressed SND1 in HCC tissues than normal tissues 50 HCC patients from online data sets HEK 293t and HepG2 (ii) SND1 induced lncRNA UCA1 expression through the interaction of SND1 [58] with MYB Hepatobiliary (i) Arsenic stress induced lncRNA UCA1 cancer (ii) LncRNA UCA1 promoted protective roles of arsenic-induced cell death by blocking autophagic flux — HepG2 [59] (iii) LncRNA UCA1 protected HCC cells against arsenic stress by repressing miR-184 and elevating OSGIN1 that activated mTOR/p70S6K autophagy inhibition pathway HCCC-9810, RBE, QBC939, Huh-28, (i) LncRNA UCA1 was overexpressed in CCA tissues and cell lines 68 CCA patients HuCCT1, KMBC, CCLP-1, and (ii) LncRNA UCA1 inhibited apoptosis through Bcl-2/caspase-3 pathway [60] HIBEC (iii) Activated AKT/GSK-3β axis elevated CCND1 expression (i) LncRNA UCA1 was highly expressed lncRNA in CCA compared with LIPF155C, CCLP1, QBC939, huh28, paracarcinoma tissues 22 CCA patients receiving surgical resection [61] and HIBEC (ii) Regulation of miR-122/CLIC1 and activation of ERK/MAPK signaling pathway (i) High expression of lncRNA UCA1 was associated with tumor size, lymph 45 GBC tissues and neighboring noncancerous tissues node metastasis, TNM stage, and short survival time in GBC patients NOZ and GBC-SD [62] from patients who underwent liver resection (ii) Recruitment of EZH2 to the promoter of p21 and E-cadherin (iii) Epigenetically suppressed p21 and E-cadherin expression 128 PC patients received operation as initial systemic Panc-1, Bxpc-3, Capan-1,SW-1990, (i) LncRNA UCA1 overexpressed in PC tissue and cell lines [63] treatment and HPDE6C-7 (ii) LncRNA UCA1 suppressed p27 protein SW1990, BxPC-3, MiaPaCa-2, (iii) Highly expressed lncRNA UCA1 in PC tissues and cell lines 50 PC patients [64] PANC-1, CAPAN-1, and HPDE (iv) LncRNA UCA1 sponged miR135a (i) Out of 19 lncRNAs, lncRNA UCA1 was one of the overexpressed lncRNAs in HPC-Y5, PANC-1, SW1990, and 36 PC patients underwent surgical resection PC tissues [65] AsPC-1 (ii) LncRNA UCA1 repressed miR-96, resulting in increased FOXO3 expression Pancreatic (i) Higher mRNA levels of lncRNA UCA1 in PC tissues than normal pancreatic cancer Analysis of mRNA levels of lncRNA UCA1 in PC patients BxPC-3, SW1990, PaTu8988, and tissues and correlated with poor prognosis [66] from BADEA and TCGA databases PANC-1 (ii) LncRNA UCA1 promoted cell migration and invasion via Hippo signaling pathway (i) LncRNA UCA1 was highly expressed in PDAC tumor specimens than normal tissue Analysis of lncRNA UCA1 mRNA levels from TCGA PaTu8902, Mpanc96, HEK293T, and (ii) LncRNA UCA1 acted as a ceRNA to increase the expression of KRAS via [67] database in PDAC tumor specimens and normal H6C7 sponging miR-590-3p (iii) KRAS promoted lncRNA UCA1 expression. 8 Journal of Oncology Table 1: Continued. Cancer type Study subject Cell line Finding/mechanistic response Reference CaCO-2, SW480, HCT116, LoVo, and (i) Overexpressed lncRNA UCA1 promoted cell proliferation, apoptosis, and 80 CRC patients [68] CCC-HIE-2 cell cycle distribution Two CRC cohorts, including 90 and 119 human primary (i) Induced 5-FU resistance HEK-293T, HCT8, HCT116, HT29, CRC tissues and their paired adjacent noncancerous (ii) Inhibition of miR-204-5p and upregulated its target genes (e.g., bcl2, rab22a, [69] LoVo, and SW480 tissues, respectively and creb1) (i) Overexpressed lncRNA UCA1 in CRC tissues and cell lines NCM460, SW620, HT29, CACO2, (ii) LncRNA UCA1 repressed miR-28-5p level, which subsequently increased 60 CRC patients [70] SW480, and HCT116 HOXB3 axis (iii) LncRNA UCA1 elevated MMP2 and MMP9 (i) Overexpressed lncRNA UCA1 in CRC cell lines CCD-18Co, HIEC-6, SW620, and (ii) LncRNA UCA1 sponged miR-185-5p, leading to elevation of WNT1 and — [71] HT29 WISP2 that activated WISP2/b-catenin signaling pathway, which affected autophagy and survival of CRC (i) Overexpressed lncRNA UCA1 in CRC cell lines SW480, SW620, HT-29, CCD-18Co, — (ii) LncRNA UCA1 elevated the expression of MAPK14 to activate [72] and HIEC-6 MAPKAPK2/HSP27 signaling pathway (i) Overexpressed lncRNA UCA1 in CRC cell lines (ii) CAFs induced lncRNA UCA1 to increase the expression of mTOR Colorectal — SW480 and NF [73] (iii) LncRNA UCA1/mTOR axis repressed p27 and miR-143 and significantly cancer elevated cyclin D1 and KRAS expression (i) LncRNA UCA1 significantly expressed higher in CRC tissue after chemoradiotherapy Tissue from 32 CRC patients collected immediately after HCT116, CCL244, SW480, LoVo, and (ii) Downregulation of LncRNA UCA1 enhanced radiotherapy sensitivity [74] surgical resection FHC (iii) LncRNA UCA1 inhibited EMT by reducing MMP2, MMP9, ZEB1, and vimentin (i) 5-fluorouracil resistance of CRC was associated with lncRNA UCA1 25 CRC patients with 5-fluorouracil resistance and 25 abundance that promoted autophagy and inhibited apoptosis SW480, SW620, and 293T [75] CRC patients with 5-fluorouracil sensitivity (ii) LncRNA UCA1 sponged miR-23b-3p and consequently elevated ZNF281 expression (i) LncRNA UCA1 levels upregulated in cetuximab-resistant cells and their exosomes (ii) Exosomal lncRNA UCA1 was detectable and stable in the serum of CRC patients 53 CRC patients treated with cetuximab Caco2-CR and Caco2-CS [76] (ii) Exosomes originated from cetuximab-resistant cells could alter lncRNA UCA1 expression (iv) LncRNA UCA1 can be transferred from resistant cells to sensitive cells through exosomes Journal of Oncology 9 ROCK1 miR-204 sox4 miR-122 clic1 TGFβ1 snail2 zeb2 EMT miR-203 miR-135a HIF-1α Chromatin kras creb1 miR-495-3p satb1 miR-590-3p modification ceRNA/ HBx miRNA sponge miR-96 foxo3 miR-28-5p hoxb3 SND1 pdl1 miR-193a mapk14 miR-185-5p wnt1 wisp2 MYB LncRNA UCA1 pdl1 miR-214 fgfr1 miR-216b CAFs miR-27b Chemoresistance rab22a bcl2 SP1 miR-204-5p creb1 SATB1 miR-7-5p egfr HXK2 caspase-3 KRAS ZNF-281 miR-23b-3p miR-531a-3p CYP1B1 HXK2 miR-203 Upregulate/promote Downregulate Figure 2: Overview of the upstream and downstream regulation of lncRNA UCA1 on miRNAs, genes, and proteins in GI cancer. LncRNA UCA1 could be induced by TGF-β1, HIF-1α, HBx, SND1-MYB complexes, CAFs, SP1, SATB1, and KRAS proteins, while ROCK1 can repress its expression. In turn, it acts as a ceRNA and an mRNA sponge that can reduce miRNA expression, which further downregulate its mediating gene expression. Collectively, lncRNA UCA1 regulates this interaction network to promote cell proliferation, metastasis, and chemoresistance in different GI cancers. LncRNA UCA1 EZH2 miR-185-5p miR-216b CLIC1 AKT3 MOB1 EIF4E GRK2 Vimentin ZO-1 YAP Lats1 p-AKT3 Snail Cbl-c E-cadherin FGFR1 p27kip1 CDK2 ERK WNT1 MAPK14 p-mTOR MAPK YAP signaling AKT/GSK- p21 S6K pathway 3B/cyclin D1 ERK-MMP9 signaling ERK WISP2/ MAPKAPK2/ EMT E-cadherin signaling β-catenin pathway HSP27 signaling pathway Hippo signaling pathway pathway PI3K-Akt-mTOR pathway signaling pathway Cancer progression/Chemoresistance Upregulate/promote Downregulate Figure 3: ,e signaling pathway associated with lncRNA UCA1 in GI cancer. LncRNA UCA1 induces EMT by regulating EMT key proteins. It also promotes the activation of PI3K/Akt/mTOR signaling pathway, ERK/MMP9 signaling pathway, ERK signaling pathway, Hippo pathway, WISP2/β-catenin signaling pathway, and MAPKAPK2/HSP27 signaling pathway by regulating their key proteins. Additionally, lncRNA UCA1 also interacts with EZH2 to regulate protein expression. that the lncRNA UCA1 may facilitate GC development, 3.3. Hepatobiliary Cancer. Hepatobiliary cancer comprises progression, and chemoresistance via the interaction with tumors present in the liver, gallbladder, and bile duct different molecules, signaling pathways, and/or miRNAs. (cholangiocarcinoma). For instance, Wang et al. showed that Cancer progression Chemoresistance 10 Journal of Oncology contributed to As-induced autophagic flux blockage through lncRNA UCA1 was highly expressed in HCC and positively correlated with postoperative survival and tumor, node, and activating mTOR/ribosomal protein S6 kinase beta-1 (p70S6K) cascade and therefore resulting in compromised cell death [59]. metastasis (TNM) stage [78]. In addition, the result also showed that lncRNA UCA1 regulated fibroblast growth Nonetheless, this finding did not directly conclude the rela- factor receptor 1 (FGFR1)/ERK signaling pathway through tionship of lncRNA UCA1 with HCC progression. However, sponging miR-216b that led to downregulation of the mRNA the arsenic stress might resemble anticytotoxicity effects as levels of miR-216b. In contrast, upregulation was detected arsenic induces cell death. ,erefore, future studies should be for fgfr1 gene to activate the ERK signaling pathway [78]. conducted in order to relate the effects of lncRNA UCA1/ One of the known risk factors for HCC is hepatitis virus OSGIN1/mTOR/p70S6K with HCC progression. On the other hand, overexpressed lncRNA UCA1 in infection [79]. Interestingly, hepatitis B virus (HBV) can induce lncRNA UCA1 in HCC cells via their produced X protein cholangiocarcinoma (CCA) showed that it could act as an independent prognostic factor in CCA patients [60]. Similar (HBx) [55]. LncRNA UCA1 also significantly reduced p27kip1 expression along with the increased expression of EZH2 via to the finding reported by Wang et al. in GC, Xu et al. also found that enhanced CCA cell proliferation was via the histone methylation on p27kip1 promoter region [55]. In addition, ectopically expressed lncRNA UCA1 induced the activation of AKT/GSK-3β axis that led to upregulation of expression of cyclin-dependent kinase-2 (CDK2) but not for cyclin D1 (CCND1) expression [50, 60]. ,e apoptosis in- CDK4 and CDK6 where CDK2 regulated cell cycle and ap- hibition in highly lncRNA UCA1-expressed CCA cells might optosis, and its activity was regulated by CDK inhibitors (e.g., be partly due to B-cell lymphoma 2 (Bcl-2)/caspase-3 p21 and p27) [55]. However, only p27 expression was sup- pathway [60]. pressed in overexpressed HBx and lncRNA UCA1 HCC cells LncRNA UCA1 has also been reported to play an im- portant role in CCA metastasis through regulating miR-122/ [55]. ,erefore, this finding suggested that the regulating effects of lncRNA UCA1 are protein-specific despite originating from chloride intracellular channel 1 (CLIC1). For instance, both lncRNA UCA1 and CLIC1 were elevated, while miR-122 was the same upstream mediators. Apart from lncRNA UCA1, TGF-β1 and HXK2 were also reduced in bile duct carcinoma [61]. Also, both lncRNA UCA1 and CLIC1 promoted the phosphorylation of ERK found to be overexpressed in HCC patients [56]. Hu et al. suggested that TGF-β1 promoted HCC cell growth through and mitogen-activated protein kinase (MAPK), activating the induction of energy metabolism and subsequently ERK/MAPK signaling pathway to promote cancer cell promoted lncRNA UCA1 expression and its downstream metastasis [61]. regulator HXK2, an isozyme that involves in glycolysis [56]. Apart from HCC and CCA, lncRNA UCA1 is also over- Most studies have reported that lncRNA UCA1 is prone to expressed in gallbladder cancer (GBC) [62]. ,e overexpressed regulate miRNA expression, but Zhao et al. revealed that lncRNA UCA1 regulated tumor progression through the re- cruitment of EZH2 to the promoter of both tumor suppressor miR-124, a tumor suppressor mRNA, reduced rho-associ- ated protein kinase 1 (ROCK1) to suppress lncRNA UCA1 p21 and E-cadherin that resulted in their suppressed expression [62]. ,is observation is opposed to what discovered in HCC expression, leading to the inhibition of HCC cell prolifer- ation, migration, and invasion [57]. ,ey further discovered by Hu et al. for p21, which could be probably explained by that the expression of both lncRNA UCA1 and miR-124 was different cancer types used. not affected by HBV and HCV infections [57]. ,is finding, In short, these findings revealed the association of however, could be correct if lncRNA UCA1 is the down- lncRNA UCA1 in tumor progression, invasion, and me- stream target protein of miR-124 or incorrect if miRNA and tastasis of hepatobiliary cancer by regulating downstream lncRNA UCA1 are negatively regulated in which miRNAs molecules or be regulated by upstream mediators. usually downregulated when lncRNA UCA1 is overex- pressed as in most cancer types reported. 3.4. Pancreatic Cancer. Pancreatic cancer (PC) is the fourth Furthermore, staphylococcal nuclease and tudor domain leading cause of cancer-related deaths worldwide [80, 81]. containing 1 (SND1) can induce the expression of lncRNA According to Chen et al., lncRNA UCA1 overexpression was UCA1 through its interaction with myeloblastosis proto- detected in the tissues of 128 pancreatic cancer patients oncogene (MYB), a transcriptional activator, by forming SND1-MYB complex [58]. Meanwhile, SND1 itself acts as an compared to adjacent nontumor tissues [63]. Moreover, lncRNA UCA1 silencing inhibited cell proliferation and in- antiapoptotic factor in HCC [58]. Again, this finding sup- ported the previous hypothesis that lncRNA UCA1 ex- duced apoptosis and cell cycle arrest in PC cells [63]. ,ey also found the possible association of lncRNA UCA1 with the pression can be induced by another gene or protein. Meanwhile, an in vitro study involving HCC cells showed inhibition of p27 in their previous study on PC [63]. In ad- dition, lncRNA UCA1 was shown to regulate growth and that lncRNA UCA1 was substantially induced by arsenic (As) at metastasis by sponging miR-135a in PC [64]. Apart from the 10 μM/L with > 4-fold increase, denoting a protective role interaction with miR-135a, lncRNA UCA1 also inhibited miR- against As-induced cell death [59]. By using RNA-Seq assay, 96, a tumor suppressor mRNA, resulting in the upregulation of oxidative stress induced growth inhibitor 1 (OSGIN1) was forkhead box O-3 (FOXO3) to promote tumor progression uncovered to be the most responsive downstream target of [65]. lncRNA UCA1, and miR-184 acted as an intermediate for the regulation of lncRNA UCA1 on OSGIN1 expression through In PC cells, lncRNA UCA1 demonstrated to promote cell migration and invasion through Hippo pathway by ceRNA mechanism [59]. ,e lncRNA UCA1/OSGIN1 signaling Journal of Oncology 11 and drug resistance, while CREB1 transcription factor involves interacting with key proteins, such as Mps one binder kinase activator (MOB1), large tumor suppressor kinase 1 (Lats1), in CRC tumorigenesis [69, 83]. In addition to miR-204-5p, creb1 is also a target gene of miR-590-3p [46]. phosphorylated-Lats1, and Yes-associated protein (YAP) [66]. LncRNA UCA1 bound to MOB1, Lats1, and YAP to Similarly, lncRNA UCA1 also inhibited miR-28-5p ac- form three shielding composites, retaining YAP activation tivity to cause the overexpression of Homeobox B3 and leading to YAP translocation into the nucleus to induce (HOXB3), promoting CRC cell proliferation and migration gene expression for cell proliferation and apoptosis and for [70]. Cui et al. revealed that both lncRNA UCA1 silencing lncRNA UCA1 expression itself [66]. Moreover, lncRNA and elevation of miR-28-5p expression reduced the protein UCA1 also interacted with MOB1, Lats1, and YAP to form levels of MMP2 and MMP9 that play a crucial role in cancer ribonucleoprotein complex that could be another reason in cell metastasis [70]. regulating gene expression. In addition, upregulation of Interestingly, lncRNA UCA1 also has an miRNA sponging activity in CRC. For instance, it sponged miR-185- MMP (e.g., MMP14, MMP2, and MMP9) proteins were also detected in lncRNA UCA1-overexpressed PC cells, sug- 5p and led to overexpressed Wnt family member 1 (WNT1) and WNT1-inducible-signaling pathway protein 2 (WISP2); gesting the role of lncRNA UCA1 in invasion and migration [66]. ,is study indicated that lncRNA UCA1 could interact both activating WISP2/β-catenin signaling pathway to with key proteins and protein complexes by binding to their regulate autophagy and survival of CRC [71]. Apart from promoter region to enhance PC cell progression. wnt1 and wisp2, mapk14 is also a target gene of miR-185-5p, In pancreatic ductal adenocarcinoma (PDAC), lncRNA where upregulation of mapk14 activated mitogen-activated UCA1 regulated miR-590-3p to increase the expression of protein kinase-activated protein kinase 2 (MAPKAPK2)/ oncogenic Kirsten rat sarcoma viral oncogene homolog heat-shock protein 27 (HSP27) signaling pathway to pro- mote invasion, migration, and EMT [72]. (KRAS) protein, and KRAS itself can promote lncRNA UCA1 expression [67]. ,is discovery showed that lncRNA ,e interplay of CRC tumor microenvironment on the expression of lncRNA UCA1 has also been studied. Jahangiri UCA1 and its downstream protein could regulate each other. Previously, Gu et al. reported that lncRNA UCA1 was as- et al. demonstrated that cancer-associated fibroblasts (CAFs) activated lncRNA UCA1 to induce mTOR overexpression [73]. sociated with miR-590-3p in GC cells via the target gene of miR-590-3p and creb1 [46]. Interestingly, Liu et al. newly ,e active lncRNA UCA1/mTOR axis subsequently reduced discovered that kras is another target gene of miR-590-3p in the expression of tumor suppressor p27 and miR-143 while PDAC [67]. ,erefore, further studies could be conducted to significantly increased cyclin D1 and KRAS expression [73]. identify miRNA target genes associated with lncRNA UCA1 Nonetheless, they further discovered that mTOR can regulate to enhance the understanding of the exact mechanism in miR-143, but whether lncRNA UCA1 could directly regulate regulating PDAC progression. the expression of miR-143 is unknown. Interestingly, it was discovered that the expression of Interesting observation by using human PDAC PANC-1 cells showed the potential of ceRNA networks, consisting of lncRNA UCA1 was significantly higher in four CRC human tissues and CCL244 CRC cells, but no significant difference was lncRNAs, circRNAs, and mRNAs, to be involved in autophagy suppression of PDAC caused by chloroquine diphosphate [82]. observed in HCT-116 CRC cells after chemoradiotherapy [74]. By using microarrays, numerous ceRNAs exhibited target as- ,is observation may indicate that lncRNA UCA1 plays a sociations with miR-663a-5p and miR-154-3p, and negative regulatory role in CRC radioresistance. Nevertheless, when associations with the expression of the targeted miRNAs under lncRNA UCA1 was silenced, it enhanced the radiotherapy the same changes in the autophagic level were determined [82]. sensitivity of CRC cells via X-ray irradiation-induced apoptosis ,e study also demonstrated that AC024560.2 competitively and prolonged G2/M cell cycle [74]. Yang et al. further showed binds to miR-663a-5p and thus regulates the autophagic level of that low level of lncRNA UCA1 inhibited EMT induction by PDAC cells by inhibiting the expression of this miRNA [82]. significantly suppressing the expression of EMT-regulating proteins, such as MMP2, MMP9, ZEB1, and vimentin [74]. In ,is shows that the ceRNAs including lncRNA could be a potential molecular target in diagnosis and treatment of PC. addition, the regulation of lncRNA UCA1 in CRC chemo- resistance is also facilitated by autophagy. For instance, it was To sum up, lncRNA UCA1 plays a significant role in PC progression that could be a novel independent predictor of shown to promote 5-fluorouracil resistance in CRC cells by the poor survival of PC patients, as well as a promising facilitating autophagy mediated by repressed miR-23b-3p and biomarker in cancer therapy. elevated zinc finger protein 281 (ZNF281) [75]. Similarly, lncRNA UCA1 also mediated autophagy to protect BC against rapamycin by inducing miR-582-5p-regulated autophagy-re- 3.5. Colorectal Cancer. Highly expressed lncRNA UCA1 is also lated protein 7 (ATG7) [84]. reported in colorectal cancer (CRC) cells and contributed to Meanwhile, Yang et al. illustrated that exosomal lncRNA tumorigenic activity [68]. For instance, overexpressed lncRNA UCA1 could be a promising biomarker for effective diag- UCA1 reduced miR-204-5p expression in CRC cells to enhance nosis and targeted therapy as exosomal lncRNA UCA1 can the expression of miR-204-5p target proteins, such as BCL2, ras- be assayed in a noninvasive manner and found to be rela- related protein (RAB22A), and CREB1 [69]. Elevated expres- tively abundant and stable in the serum of CRC patients [76]. sion of BCL2 and RAB22A can promote CRC cell proliferation To note, exosomes originated from cetuximab-resistance cell 12 Journal of Oncology against various cancers, including GI cancer [88–90]. In con- can alter the expression of lncRNA UCA1 and enhance resistance to cetuximab in CRC cells in view of the fact that clusion, lncRNA UCA1 has been identified as a novel and potential molecular target for GI cancer in the last decade based lncRNA UCA1 can transmit cetuximab resistance to sen- sitive cells [76]. Given this circumstance, exosomal lncRNA on its potent regulatory roles in cancer progression and che- UCA1 indeed has a great potential to be used as an evalu- moresistance. However, to enhance its translation possibility to ation factor for predicting cetuximab chemoresistance in clinical trials, more preclinical studies using both in vitro and in CRC patients. vivo models should be conducted to further explore the key In summary, lncRNA UCA1 participated significantly in mechanism of actions underlying its regulatory roles. Also, the CRC progression, invasion, migration, metastasis, lncRNA UCA1, particularly enriched in exosomes, can be a radioresistance, and chemoresistance. ,erefore, lncRNA potential diagnostic and prognostic biomarker compared to UCA1 can be a promising molecular target to combat CRC other molecular targets due to its high stability and availability in various human body fluids, including urine for BC [13], in chemotherapy, as well as in diagnostic and prognostic purpose of CRC patients. serum for HCC [91], and plasma sample in early GC [42], as well as its possible simplicity of extraction and diagnostic testing procedures. 4. Conclusion ,is review has provided an insight into the regulatory roles Data Availability and patterns of lncRNA UCA1 in GI cancer progression and chemoresistance, as well as its underlying mechanisms and ,e data supporting this manuscript are extracted from the interaction with key molecules involved, which may serve as previously reported studies and data sets, which have all a novel and highly potential molecular target for GI cancer been cited. therapy. It has discovered that multiple preclinical and clinical studies supporting the oncogenic role of lncRNA Conflicts of Interest UCA1 in GI cancer. In addition, the potential of lncRNA ,e authors declare that they have no conflicts of interest. UCA1 to be used as a prognostic marker has also been reported in several studies, where its expression correlates with the TNM stage of GI cancer [85]. Based on the findings Authors’ Contributions in this review, it was revealed that basic overexpression of lncRNA UCA1 has a positive implication in initiation, All authors contributed equally to this paper. proliferation, invasion, migration, and chemoresistance of GI cancer, although contradictory findings claim that it also Acknowledgments has anticancer activity, via the interactions with upstream and/or downstream molecules, signaling pathways, or bio- ,is work was supported by the Fundamental Research Grant Scheme (project no. FRGS/1/2019/SKK10/MAHSA/ logical processes. ,e regulatory roles of lncRNA UCA1 in 03/1) and MAHSA University research grant (project no. GI cancer progression are relatively observed more in GC RP165-05/19). followed by CRC. Comparatively, the regulation of che- moresistance by lncRNA UCA1 has so far discovered only in GC and CRC [16]. In general, lncRNA UCA1 interacts with References miRNAs, leading to the reduction of its target gene ex- [1] J. C. 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Published: Apr 12, 2021

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