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Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An Integrated Analysis of the Immunohistochemical Study and Bioinformatics Analysis

Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An... Hindawi Journal of Oncology Volume 2020, Article ID 3761535, 11 pages https://doi.org/10.1155/2020/3761535 Research Article Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An Integrated Analysis of the Immunohistochemical Study and Bioinformatics Analysis 1 1 1 2 Kun Song, Jingduo Hao, Zuyin Ge, and Pushi Chen Department of General Surgery, People's Hospital of Zhenhai, Ningbo, Zhejiang 315202, China Health Management Center, Ningbo First Hospital, Ningbo, Zhejiang 315000, China Correspondence should be addressed to Pushi Chen; 314287075@qq.com Received 14 August 2019; Revised 30 November 2019; Accepted 30 December 2019; Published 13 February 2020 Academic Editor: Rossana Berardi Copyright © 2020 Kun Song 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. Transcription factor sex-determining region Y-box 2 (SOX2) involves in the maintenance of cancer stem cells. However, the role of SOX2 in colorectal cancer (CRC) remains unclear. -is study was conducted to investigate the effect of SOX2 on CRC. Studies were searched using electronic databases. -e combined odds ratios (ORs) or hazard ratios (HRs: multivariate Cox survival analysis) with their 95% confidence intervals (CIs) were calculated. -e Cancer Genome Atlas (TCGA) and GEO datasets were further applied to validate the survival effect. -e functional analysis of SOX2 was investigated. In this work, 13 studies including 2337 patients were identified, and validation data were enrolled from TCGA and GEO datasets. SOX2 expression was not significantly related to age, gender, microsatellite instability (MSI) status, clinical stage, histological grade, tumor size, pT-stage, lymph node metastasis, distal metastasis, and cancer-specific survival (CSS) but was correlated with worse overall survival (OS: n � 536 patients) (P< 0.05). Furthermore, TCGA data demonstrated similar results, with no significant correlation between SOX2 and pathological characteristics. Further validation data (OS: n � 1408 and disease-free survival (DFS): n � 1367) showed that SOX2 expression was correlated with worse OS (HR � 1.35, 95% CI: 1.11–1.65, P � 0.004) and DFS (HR � 1.30, 95% CI: 1.04–1.62, P � 0.02). -e functional analyses showed that SOX2 involved in cell-cell junction, focal adhesion, extracellular matrix- (ECM-) receptor interaction, and MAP kinase activity. Our findings suggest that SOX2 expression may be correlated with the worse prognosis of CRC. renewal and multilineage differentiation and proliferation 1. Introduction potential, which are related to tumor progression, metas- Colorectal cancer (CRC) is one of the most common ma- tasis, recurrence, prognosis, and drug resistance [6–8]. Many lignant tumors and a major cause of cancer-related death in CSC-related markers have been identified and reported to be the world and in China [1, 2]. According to the GLOBOCAN associated with poor prognosis and resistance to therapy in estimates, approximately 1,800,977 new cases were diag- cancer [9, 10]. Sex-determining region Y-box 2 (SOX2), a nosed with CRC, leading to approximately 861,663 deaths high mobility group (HMG) DNA-binding domain, is due to this disease in 2018 worldwide [1]. Although some mapped to human chromosome 3q26.3–q27 and belongs to significant achievements have been made in early detection a key transcription factor [11]. SOX2 regulates the self-re- and treatment in recent years, most patients are diagnosed newal and pluripotency of undifferentiated stem cells such as with advanced disease and show a poor 5-year survival rate human embryonic stem cells and plays an important role in [3–5]. -erefore, it is needed to find new efficient bio- maintaining the stem cell–like features in cancer cells markers for the treatment of CRC along with the prognosis. [12–14]. Additionally, SOX2 involves in the migration, in- Cancer stem cells (CSCs) are a special subpopulation of vasion, and proliferation of cancer cells and resistance to tumor cells and have the ability and characteristics of self- therapy [15, 16]. SOX2 has been reported to be commonly 2 Journal of Oncology expressed in many human cancers, such as breast cancer, same institute were published. We mainly excluded review lung cancer, esophageal cancer, and CRC [17]. For example, articles, letters, conference abstracts, case reports, cell line/ animal studies, and articles lacking sufficient data. SOX2 expression is correlated with worse prognosis in breast cancer and gastric cancer [18, 19]. While SOX2 expression shows a favorable prognosis in non-small cell lung cancer 2.3. Data Extraction and Study Quality Assessment. -e and cervical cancer [20, 21]. -erefore, it is of great im- portance to determine the prognostic role of SOX2 ex- relevant data and search of the included studies were conducted from two independent authors (KS and JH) using pression in CRC. -e previous meta-analysis only included eight studies standardized forms, including the surname of the first au- thor, time of publication, country, ethnicity, median/mean with small sample sizes (n � 1113) and only analyzed the correlation between SOX2 and overall survival (OS) and a age, disease stage, antibody information, number of par- ticipants, cutoff values of SOX2, expression frequency, small part of the clinical features of CRC. Additionally, the clinicopathological parameters such as age, gender, micro- result on OS was not reasonable [22]. -erefore, the sig- satellite instability (MSI) status, clinical stage, histological nificance of SOX2 expression in CRC is not fully understood. grade, tumor size, pT-stage, lymph node metastasis, and For example, Lundberg et al. reported that SOX2 expression was not related to cancer-specific survival in CRC [23], but distal metastasis, and the survival data of multivariate Cox analysis such as cancer-specific survival (CSS), overall SOX2 expression was correlated with worse cancer-specific survival by Miller et al. [24]. -us, the current work with survival (OS), and disease-free survival (DFS). -e quality of the available publications was assessed according to the 3745 CRCs was performed to determine the survival impact of SOX2 expression on CRC ((cancer-specific survival (CSS), Newcastle–Ottawa Scale (NOS) for cohort studies [26, 27]. -ree parameters of quality included a total of nine scores: overall survival (OS), and disease-free survival (DFS)) and to evaluate the association between SOX2 expression and selection (0–4), comparability (0–2), and outcome assess- ment (0–3). In this meta-analysis, the publication with ≥6 general clinicopathological characteristics. scores was considered to be of high quality, and the NOS score with <6 was defined as low-quality study. Any dis- 2. Materials and Methods agreements in the selected literature were discussed by all authors and then reached a consensus. 2.1. Literature Search. -is meta-analysis was performed based on the Preferred Reporting Items for Systematic re- views and Meta-Analyses (PRISMA) statement [25] (Sup- 2.4. Validation Data from TCGA. -e RNA-sequencing data plementary Materials). -e electronic databases PubMed, and corresponding clinical information on CRC were ob- EMBASE, and Web of Science were comprehensively tained from -e Cancer Genome Atlas (TCGA) (https:// searched to identify eligible publications until July 29, 2019, portal.gdc.cancer.gov/repository). Eventually, 618 cases with by searching the following key words and search terms: CRC with sufficient expression data and clinical information “colorectal cancer OR colorectal tumor OR colorectal car- were selected. cinoma OR colorectal neoplasm OR CRC OR rectal cancer OR rectal tumor OR rectal carcinoma OR colon cancer OR colon tumor OR colon carcinoma” and “SOX2 OR SOX-2 2.5. Functional Analysis of SOX2. Association between SOX2 OR Sex-determining region Y-box protein 2 OR Sex de- and genes was analyzed using TCGA sequencing data. termining region Y box-2 OR Sex-determining region Y-box Spearman coefficients with an absolute value of >0.2 and 2 OR SRY box-2” (Supplementary Materials). Moreover, the P< 0.001 were applied for SOX2. -e potential function and reference lists of the identified articles were also examined to biological mechanism of the SOX2 gene such as GO (Gene find other relevant studies. Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were investigated by clusterProfiler package. 2.2. Eligibility Criteria. For the enrollment of publications, the main inclusion criteria were included as follows: (1) the patients with CRC were reported; (2) studies reported the 2.6. Survival Analysis from Validation Datasets. detection of SOX2 using immunohistochemistry (IHC); (3) Normalized GSE17538 (n � 232 patients), GSE39582 expression status of SOX2 was defined from the original (n � 558 patients), and TCGA (n � 618 patients) datasets articles; (4) studies provided available data to assess the were applied due to sufficient survival information and the correlation between SOX2 expression and clinicopatho- batch effects were adjusted using the ComBat method logical parameters; (5) studies provided sufficient hazard [28, 29]. Finally, 1408 CRC patients were used to further ratio (HR) with 95% confidence interval (CI) to evaluate the confirm whether SOX2 expression was still correlated with prognostic impact of SOX2 expression on CRC patients worse OS and 1367 CRC patients were used to further based on multivariate Cox survival analysis. If the results of validate whether SOX2 expression was still related to dis- interest were not completely reported, the corresponding ease-free survival (DFS). -e optimal cutoff value (SOX2: author will be contacted via e-mail. Only the recent article or 3.31) was selected and survival analysis was performed using the article with the most complete data was selected when “survival and survminer” packages. multiple articles using overlapping tissue samples from the Journal of Oncology 3 Records identified through Additional records identified database searching through other sources (n = 927) (n = 6) Records after duplicates removed (n = 513) Records excluded (n = 447): irrelevant title or abstract Records screened studies on cell lines or (n = 513) animals Full-text articles assessed Full-text articles excluded: for eligibility insufficient data based on (n = 66) the selection criteria (n = 53) Studies included in qualitative synthesis (n = 13) Studies included in quantitative synthesis (meta-analysis) (n = 13) Figure 1: Flow diagram of the study selection process. 2.7. Statistical Analysis. Data on meta-analysis were ob- For bioinformatics validation data, the TCGA patients were divided into positive and negative groups based on the tained from the original articles. -e pooled odds ratios (ORs) and the corresponding 95% CIs were calculated to median value of SOX2 expression. -e relationships between assess the relationship of SOX2 expression with the clini- SOX2 expression and the clinicopathological parameters copathological parameters. -e pooled HRs with their 95% were performed using the univariate logistic regression CIs were performed to estimate the prognostic impact of analysis. -e clinicopathological parameters included age, SOX2 expression on CRC patients using multivariate Cox MSI status, clinical stage, lymph node metastasis, distal survival analysis. As described in the report of IntHout et al., metastasis, venous invasion, and lymphatic invasion. the Hartung–Knapp–Sidik–Jonkman (HKSJ) method was Analysis for validation data was performed by using R applied to improve the reliability of the pooled results with version 3.5.1 [R Core Team, 2018]. ≤10 studies in the current meta-analysis [30]. -e hetero- geneity assumption between studies was measured using 3. Results Cochran’s Q statistic [31]. A Q test of P< 0.1 was considered to be a significant heterogeneity. When substantial het- 3.1. Study Characteristics. -e flow diagram for the study erogeneity was detected, sensitivity analyses were conducted selection is presented in Figure 1. Based on the selection to estimate the change of heterogeneity and stability of an criteria, inappropriate studies were excluded. Finally, 13 individual study on the recalculated results by removing a studies published between 2010 and 2019 were identified in single study [32]. -e possible publication bias was per- the present meta-analysis [6, 14, 23, 24, 34–42], including formed by Egger’s test [33]. -e pooled ORs and HRs were 2337 patients with CRC. Eligible studies were conducted in calculated using “metafor” package via R version 3.5.1 [R China, Korea, Singapore, Australia, Germany, Sweden, and Core Team, 2018]. Results of publication bias were carried -e Netherlands. Among these studies, expression of SOX2 out using Stata software (version 12.0, Stata Corporation, was evaluated by IHC. 10 studies with 1431 cases evaluated College Station, TX, US). -e code for the relevant examples the relationship between SOX2 expression and the clini- is listed in Supplementary Materials. copathological parameters [14, 23, 24, 35–41]. Five studies Screening Included Eligibility Identification 4 Journal of Oncology Table 1: Main characteristics of the eligible publications. Cutoff Cancer Clinical Survival- First author Country Age Stage Antibody Sources of antibody Staining values Total features MA (IHC) (E+ %) Clone 57CT23.3.4; Ong et al. Anti- 310 Singapore NA 1–4 Abcam, Cambridge, Cytoplasm 10% No CSS [42] SOX2 (NA) MA Clone D6D9, cell Neumann Anti- 114 Germany 66.5 NA Signaling technology, Nuclei 10% Yes NA et al. [41] SOX2 (21.1%) Danvers, MA Han et al. Anti- 44 China NA NA Epitomics NA NA Yes NA [40] SOX2 (20.5%) Anti- Abcam, Cambridge, 110 Lee et al. [39] Korea NA 1–4 Nuclei 5% Yes NA SOX2 UK (17.3%) Anti- Cell Signaling 67 Liu et al. [43] China NA 1–4 Nuclei ≥2 scores Yes NA SOX2 Technology, Inc (22.4%) Anti- ab75485, Abcam, 89 Ma et al. [38] China 65 1–4 NA >1.40 Yes NA SOX2 Cambridge, MA (50.6%) Raghoebir -e Anti- 135 NA NA Immune systems Nuclei 5% Yes NA et al. [37] Netherlands SOX2 (20.7%) Lundberg Anti- Abcam, Cambridge, 441 Sweden NA 1–4 Nuclei NA Yes CSS et al. [23] SOX2 UK (10.7%) Yan et al. Anti- 280 China 65 3–4 Abcam NA 2.5 Yes NA [36] SOX2 (41.8%) EPR3131; Abcam cell Miller et al. Anti- 104 Australia 66.7 3 Signaling Technology, Nuclei NA Yes CSS, OS [24] SOX2 (18.3%) Danvers Zheng et al. Anti- Mass cat. no. 636675, 47 China NA 1–4 NA NA Yes NA [35] SOX2 EMD Millipore (80.9%) Han et al. Anti- 164 Korea 59.8 3 Billerica, MA, USA NA ≥1 score No DFS [44] SOX2 (82.3%) Anti- 432 Li et al. [34] China NA 1–4 #ab92494 NA NA No OS SOX2 (NA) NA: not applicable; IHC: immunohistochemistry; E+: positive/high expression; MA: multivariate Cox analysis; DFS: disease-free survival; OS: overall survival; CSS: cancer-specific survival. Table 2: Summary of results from this meta-analysis. Variables OR [95% CI] Heterogeneity (p) t value P value Studies Cases Age (≥60 vs.< 60 years) 0.80 [0.13, 4.77] 0.618 − 1.621 0.352 2 530 Gender (male vs. female) 0.91 [0.51, 1.64] 0.138 − 0.439 0.684 5 991 MSI status (MSI vs. MSS) 1.40 [0.66, 3.00] 0.513 1.422 0.25 4 775 Clinical stage (stages 3-4 vs. 1-2) 1.34 [0.32, 5.64] 0.028 0.647 0.564 4 619 Histological grade (grades 3-4 vs. 1-2) 1.65 [0.62, 4.33] 0.004 1.428 0.227 5 999 Tumor size (≥5 vs. ≤5 cm) 0.78 [0.00, 1913.29] 0.018 − 0.398 0.759 2 347 pT-stage (T 3-4 vs. 1-2) 1.12 [0.36, 3.43] 0.065 0.308 0.778 4 526 Lymph node metastasis (yes vs. no) 3.19 [0.58, 17.66] 0.368 2.916 0.1 3 225 Distal metastasis (yes vs. no) 1.26 [0.14, 10.91] 0.015 0.454 0.694 3 438 OR: odds ratio; CI: confidence interval; MSI: microsatellite instability; MSS: microsatellite stability. with 1451 cases assessed the association between SOX2 OR � 0.80, P � 0.352), gender (five studies with 991 cases, expression and the prognosis using multivariate Cox sur- male vs. female: OR � 0.91, P � 0.684), MSI status (four vival analysis [6, 23, 24, 34, 42]. 13 studies were considered to studies with 775 cases, MSI vs. microsatellite stability (MSS): be of high quality by using NOS. -e details of the included OR � 1.40, P � 0.25) (Figure 2). studies are summarized in Table 1 and Table S1. No correlation was found between SOX2 expression and clinical stage (four studies with 619 cases, stages 3-4 vs. 1-2: OR � 1.34, P � 0.564) and histological grade (five studies with 3.2. Correlation of SOX2 Expression with Clinicopathological 999 cases, grades 3-4 vs. 1-2: OR � 1.65, P � 0.227) (Figure 3). Variables. A summary of the calculated results is shown in No relationship was observed between SOX2 expression Table 2. No association was found between SOX2 expression and tumor size (two studies with 347 cases, ≥5 vs. ≤5 cm: and age (two studies with 530 cases, ≥60 vs. <60 years: OR � 0.78, P � 0.759), pT-stage (four studies with 526 cases, Journal of Oncology 5 Studies (age) Studies (gender) OR [95% CI] OR [95% CI] Neumann et al. [41] 1.82 [0.72, 4.59] Ma et al. [38] 0.94 [0.40, 2.23] Liu et al. [43] 1.72 [0.48, 6.14] Ma et al. [38] 1.27 [0.52, 3.05] Lundberg et al. [23] 0.71 [0.34, 1.46] Lundberg et al. [23] 0.51 [0.28, 0.95] Yan et al. [36] 0.89 [0.55, 1.43] FE model 0.80 [0.13, 4.77] FE model 0.91 [0.51, 1.64] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (a) (b) Studies (MSI) OR [95% CI] Lee et al. [39] 1.71 [0.42, 7.01] Raghoebir et al. [37] 0.88 [0.27, 2.87] Lundberg et al. [23] 1.16 [0.51, 2.61] Miller et al. [24] 2.81 [0.89, 8.81] FE model 1.40 [0.66, 3.00] 0.05 0.25 1 4 Odds ratio (log scale) (c) Figure 2: Forest plot for the correlation between SOX2 and age, gender, and MSI status. (a) Age (≥60 vs. <60 years); (b) gender (male vs. female); (c) MSI status (MSI vs. MSS). OR: odds ratio; CI: confidence interval; MSS: microsatellite stability; MSI: microsatellite instability. pT-stages 3-4 vs. 1-2: OR � 1.12, P � 0.778), lymph node was significantly correlated with the histological grade metastasis (three studies with 225 cases, yes vs. no: (OR � 2.70, 95% CI � 1.15–6.37, P � 0.035), with no het- OR � 3.19, P � 0.1), and distal metastasis (three studies with erogeneity (P � 0.250). 438 cases, yes vs. no: OR � 1.26, P � 0.694) (Figure 3). 3.5. Publication Bias. No publication bias was found be- 3.3. Survival Impact of SOX2 Expression Using Multivariate tween SOX2 expression and gender and histological grade Cox Analysis. Data showed that SOX2 expression was not (P> 0.1) (Figure S1). correlated with cancer-specific survival (CSS) of CRC in three studies with 855 patients (HR � 1.18, P � 0.667) (Figure 4) but was correlated with worse overall survival 3.6. TCGA. Six hundred eighteen cases with CRC were (OS) in two studies with 536 patients (P< 0.05) [24, 34]. enrolled from TCGA. As shown in Table 3, the results using univariate logistic regression analysis showed that SOX2 3.4. Heterogeneity Analysis. Heterogeneity analysis was expression was not significantly associated with age (≥60 vs.<60 years: OR � 1.03, 95% CI � 0.73–1.46, P � 0.859), MSI conducted between SOX2 expression and clinical stage, histological grade, and pT-stage. We conducted sensitivity status (MSI vs. MSS : OR � 1.08, 95% CI � 0.77–1.52, P � 0.663), clinical stage (stages 3-4 vs. 1-2: OR � 1.37, 95% analyses to estimate the change of the pooled results. When the study of Lundberg et al. [23] was deleted, the recalculated CI � 0.99–1.89, P � 0.059), venous invasion (yes vs. no: OR was still not correlated with the clinical stage (OR � 0.55, OR � 1.12, 95% CI � 0.75–1.65, P � 0.585), lymphatic inva- 95% CI � 0.06–4.66, P � 0.350), with no evidence of het- sion (yes vs. no: OR � 1.27, 95% CI � 0.91–1.79, P � 0.162), erogeneity (P � 0.272). When the study of Han et al. [40] lymph node metastasis (yes vs. no: OR � 1.37, 95% was omitted, the recalculated result was still not associated CI � 0.99–1.88, P � 0.057), and distal metastasis (yes vs. no: with the pT-stage (OR � 1.04, 95% CI � 0.30–3.54, OR � 1.13, 95% CI � 0.72–1.79, P � 0.597), but SOX2 ex- P � 0.908), with no heterogeneity (P � 0.216). When the pression was correlated with gender (male vs. female: study of Yan et al. [36] was removed, the recalculated result OR � 0.69, 95% CI � 0.5–0.94, P � 0.02). 6 Journal of Oncology Studies (clinical stage) OR [95% CI] Studies (tumor grade) OR [95% CI] Neumann et al. [41] 1.70 [0.64, 4.50] Lundberg et al. [23] 2.18 [1.16, 4.11] Liu et al. [43] 2.00 [0.60, 6.70] Liu et al. [43] 1.02 [0.32, 3.23] Yan et al. [36] 0.80 [0.46, 1.38] Ma et al. [38] 0.28 [0.07, 1.17] Lundberg et al. [23] 2.57 [1.34, 4.96] Zheng et al. [35] 0.16 [0.01, 3.08] Miller et al. [24] 7.04 [2.37, 20.93] FE model 1.34 [0.32, 5.64] FE model 1.65 [0.62, 4.33] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (a) (b) Studies (pT-stage) OR [95% CI] Studies (N status) OR [95% CI] Han et al. [40] 22.45 [1.21, 415.67] Neumann et al. [41] 4.15 [1.43, 12.09] Neumann et al. [41] 7.80 [0.45, 136.63] Han et al. [40] 7.56 [0.85, 66.97] Ma et al. [38] 1.72 [0.56, 5.33] Liu et al. [43] 1.53 [0.40, 5.81] Yan et al. [36] 0.88 [0.54, 1.46] FE model 3.19 [0.58, 17.66] FE model 1.12 [0.36, 3.43] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (c) (d) Studies (M status) OR [95% CI] Neumann et al. [41] 3.04 [1.15, 8.04] Han et al. [40] 5.25 [0.95, 29.05] Yan et al. [36] 0.78 [0.44, 1.39] FE model 1.26 [0.14, 10.91] 0.05 0.25 1 4 Odds ratio (log scale) (e) Figure 3: Forest plot for the correlation between SOX2 and clinical stage, histological grade, pT-stage, lymph node metastasis, and distal metastasis. (a) Clinical stage: stages 3-4 vs. 1-2; (b) tumor grade: grades 3-4 vs. 1-2; (c) pT-stage: T 3-4 vs. 1-2; (d) lymph node metastasis (N status): yes vs. no; (e) distal metastasis (M status): yes vs. no. OR: odds ratio; CI: confidence interval. 3.7. SOX2 Involves in Some Key Molecular Functions in CRC. these pathways are closely associated with cancer GO and KEGG analyses showed that SOX2 involved in cell- development. cell junction, focal adhesion, extracellular matrix- (ECM-) receptor interaction, transmembrane receptor protein ty- 3.8. Further Survival Analysis from Validation Data. -e rosine kinase activity, transmembrane-ephrin receptor ac- tivity, semaphorin receptor activity, MAP kinase activity, validation data included 1408 patients with CRC, and the result also confirmed that SOX2 expression was significantly mitogen-activated protein kinase binding, transmembrane associated with worse OS (HR � 1.35, 95% CI: 1.11–1.65, receptor protein kinase activity, etc. in CRC (Figure 5), and Journal of Oncology 7 Studies HR [95% CI] Ong et al. [42] 1.03 [0.72, 1.48] Lundberg et al. [23] 1.04 [0.65, 1.67] Miller et al. [24] 6.19 [2.24, 17.10] FE model 1.18 [0.28, 4.89] 0.05 0.25 1 4 Observed outcome Figure 4: Forest plot for the correlation between SOX2 and cancer patients’ prognosis using multivariate cox analysis in cancer-specific survival (CSS). HR: hazard ratio; CI: confidence interval. Table 3: Correlation of SOX2 with the clinicopathological characteristics from the cancer genome atlas. Variables Comparison OR with 95% CI P Cases Age ≥60 vs. <60 years 1.03 (0.73–1.46) 0.859 618 Gender Male vs. female 0.69 (0.5–0.94) 0.02 618 MSI status MSI vs. MSS 1.08 (0.77–1.52) 0.663 618 Clinical stage Stages 3-4 vs. 1-2 1.37 (0.99–1.89) 0.059 598 Venous invasion Yes vs. no 1.12 (0.75–1.65) 0.585 536 Lymphatic invasion Yes vs. no 1.27 (0.91–1.79) 0.162 557 Lymph node metastasis Yes vs. no 1.37 (0.99–1.88) 0.057 615 Distal metastasis Yes vs. no 1.13 (0.72–1.79) 0.597 545 OR: odds ratio; CI: confidence interval; MSI: microsatellite instability; MSS: microsatellite stability. P � 0.004) (Figure 6(a)). Further validation data with 1367 impact in patients with CRC are still largely uncertain. In the CRC patients were used, and the result showed that SOX2 present work, we determined the clinicopathological effect of SOX2 and its expression on the prognostic impact of expression was associated with worse DFS (HR � 1.30, 95% CI: 1.04–1.62, P � 0.02) (Figure 6(b)). patients with CRC. -e relationships between SOX2 expression and the clinicopathological characteristics of CRC were investigated. 4. Discussion -e pooled data showed that SOX2 expression was not CSCs contribute to tumor metastasis and prognosis and correlated with age and MSI status, which were consistent with the previous studies on age [23, 38] and MSI status therapeutic resistance [45, 46]. CSCs may offer new promising therapeutic targets of treatment modalities ap- [23, 24, 37, 39]. Further TCGA also showed no correlation plicable to human various cancers [47, 48]. SOX2 involves in with age and MSI status. Although no correlation was found the development and maintenance of stem-like properties in between SOX2 expression and gender among all eligible cancer cells [14, 15]. SOX2 involves in many signaling studies, a large population with 441 cases reported that SOX2 expression was negatively correlated with gender and was pathways such as VEGF, MAPK, Notch, P53, Wnt, and Jak- STAT, regulates many expression of genes, and regulates lower in males than in females [23]. Further data from TCGA also demonstrated a negative association with gen- self-renewal and differentiation of stem cells, which may contribute to migration, invasion, and proliferation of der, suggesting that more studies with larger sample sizes are needed to confirm this controversial finding. SOX2 ex- cancer cells and the stemness of cancer stem cells, thereby affecting cancer progression, prognosis, and resistance to- pression was not associated with clinical stage, histological ward anticancer therapies [14, 15, 17]. SOX2 expression is grade, tumor size, pT-stage, lymph node metastasis, and found across a wide range of human cancers such as breast distal metastasis, which were in line with the previous cancer, lung cancer, and esophageal cancer [17]. SOX2 publications regarding clinical stage [14, 35, 38], histological grade [14, 36, 41], tumor size [36], pT-stage [36, 38, 41], expression is correlated with the prognosis of some human cancers such as non-small cell lung cancer and cervical lymph node metastasis [14, 40], and distal metastasis [36]. Moreover, TCGA data also confirmed no significant asso- cancer with better prognosis [20, 21] and breast cancer and gastric cancer with worse prognosis [18, 19]. Studies have ciation with clinical stage, lymph node metastasis, and distal metastasis. -ese results suggested that SOX2 expression reported that SOX2 is frequently expression in CRC [6, 34, 35]. However, the function of SOX2 and its survival was not significantly associated with progression and BP CC MF 8 Journal of Oncology p.adjust p.adjust 6e − 06 Axon development Axonogenesis Positive regulation of nervous system development 7e − 06 Synapse organization Axon guidance 8e − 06 Neuron projection guidance Heart contraction Heart process 0.01 9e −06 Regulation of heart contraction Gliogenesis 1e − 05 Neuronal cell body 0 5 101520 Postsynapse Actin cytoskeleton 0.02 Cell-cell junction Axon part Receptor complex Contractile fiber part Contractile fiber Site of polarized growth Sarcolemma 0.03 Actin binding Sulfur compound binding Actin filament binding Structural constituent of cytoskeleton Transmembrane receptor protein tyrosine kinase activity Transmembrane receptor protein kinase activity 0.04 Mitogen-activated protein kinase kinase binding Map kinase kinase kinase activity Semaphorin receptor activity Transmembrane-ephrin receptor activity 0.025 0.050 0.075 0.100 Generatio Count 10 30 20 40 (a) (b) Figure 5: SOX2 involves in some cancer mechanisms, (a) GO (gene ontology) analysis; (b) KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. metastasis of CRC. Further relevant studies are necessary to the main ethnic population was Asian and European; other confirm our results in the future. ethnic groups, such as Africans, were lacking. -ird, due to -e survival impact of SOX2 expression in patients with fewer studies, subgroups were insufficient and meta-re- CRC was performed based on multivariate Cox analysis. gression analysis was not performed. However, heteroge- SOX2 expression was not correlated with CSS but was neity analysis was carried out based on sensitivity analysis significantly associated with worse OS in CRC. Additionally, and the detailed reasons for the potential heterogeneity were further validation data from TCGA and GEO datasets (OS: not very certain. -e possible use of the inappropriate and n � 1408 CRC patients and DFS: 1367 CRC patients) different conditions of IHC methods such as different/un- clear cutoff values of SOX2 expression and different sources demonstrated that SOX2 expression was significantly cor- related with worse OS (HR � 1.35, P � 0.004) and DFS of anti-SOX2 antibody may lead to the potential sources of (HR � 1.30, P � 0.02). -ese analyses suggested that SOX2 heterogeneity. For example, in the future, the expression of was an independent prognostic marker for predicting poor SOX2 is defined as positive or negative, which should be prognosis. Additionally, the functional analysis showed that recommended using a uniform standard. Fourth, only Han SOX2 involved in cell-cell junction, focal adhesion, extra- et al. reported that SOX2 expression was correlated with DFS cellular matrix- (ECM-) receptor interaction, transmem- in 164 CRC cases (HR � 2.558, P � 0.020) [6]. Finally, brane receptor protein tyrosine kinase activity, sample sizes on the analyses between SOX2 expression and transmembrane-ephrin receptor activity, semaphorin re- the clinicopathological features and the prognosis were ceptor activity, mitogen− activated protein kinase binding, relatively small in the meta-analysis, more studies with large transmembrane receptor protein kinase activity, MAP ki- study population are necessary to further determine whether nase activity, etc., which further suggested that SOX2 may be SOX2 is correlated with clinical and prognostic value in CRC closely linked with CRC prognosis. based on IHC methods. -ere are several limitations in the present study. First, In conclusion, the current study suggested that SOX2 this meta-analysis has not been registered online. Second, expression was not significantly correlated with age, gender, ECM− receptor Focal interaction adhesion Journal of Oncology 9 1.00 SOX2 (P = 0.020) 1.0 0.75 0.8 0.50 0.6 0.4 P = 0.004 0.25 Hazard ratio = 1.35 Hazard ratio = 1.30 95% CI: 1.11 − 1.65 0.2 95% CI: 1.04 – 1.62 0.00 0.0 0 50 100 150 200 0 50 100 150 200 Time Time (months) SOX2 High (n = 839) High (859) Low (n = 528) Low (549) (a) (b) Figure 6: Survival analysis of SOX2 expression from validation data. (a) Overall survival (OS) in 1408 patients; (b) disease-free survival (DFS) in 1367 patients. MSI status, clinical stage, histological grade, tumor size, pT- Acknowledgments stage, lymph node metastasis, distal metastasis, and CSS but -e authors gratefully acknowledge -e Cancer Genome was associated with worse OS and DFS. Our data suggested Atlas and Gene Expression Omnibus. that SOX2 may be used as an independent prognostic marker for worse prognosis in CRC. More large-scale prospective studies with larger sample sizes are required to Supplementary Materials further validate these findings. Table S1: data of the eligible publications with the clinico- Data Availability pathological characteristics. Figure S1: publication bias using Egger’s test. PRISMA 2009 Checklist Search terms Code for Data are available in this manuscript. example. (Supplementary Materials) Ethical Approval References All data collection and processing, including the consenting [1] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, process, were performed after approval by all local insti- and A. 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Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An Integrated Analysis of the Immunohistochemical Study and Bioinformatics Analysis

Song, Kun; Hao, Jingduo; Ge, Zuyin; Chen, Pushi
Journal of Oncology , Volume 2020 – Feb 13, 2020
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Copyright © 2020 Kun Song 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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10.1155/2020/3761535
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Abstract

Hindawi Journal of Oncology Volume 2020, Article ID 3761535, 11 pages https://doi.org/10.1155/2020/3761535 Research Article Clinical and Survival Impact of Sex-Determining Region Y-Box 2 in Colorectal Cancer: An Integrated Analysis of the Immunohistochemical Study and Bioinformatics Analysis 1 1 1 2 Kun Song, Jingduo Hao, Zuyin Ge, and Pushi Chen Department of General Surgery, People's Hospital of Zhenhai, Ningbo, Zhejiang 315202, China Health Management Center, Ningbo First Hospital, Ningbo, Zhejiang 315000, China Correspondence should be addressed to Pushi Chen; 314287075@qq.com Received 14 August 2019; Revised 30 November 2019; Accepted 30 December 2019; Published 13 February 2020 Academic Editor: Rossana Berardi Copyright © 2020 Kun Song 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. Transcription factor sex-determining region Y-box 2 (SOX2) involves in the maintenance of cancer stem cells. However, the role of SOX2 in colorectal cancer (CRC) remains unclear. -is study was conducted to investigate the effect of SOX2 on CRC. Studies were searched using electronic databases. -e combined odds ratios (ORs) or hazard ratios (HRs: multivariate Cox survival analysis) with their 95% confidence intervals (CIs) were calculated. -e Cancer Genome Atlas (TCGA) and GEO datasets were further applied to validate the survival effect. -e functional analysis of SOX2 was investigated. In this work, 13 studies including 2337 patients were identified, and validation data were enrolled from TCGA and GEO datasets. SOX2 expression was not significantly related to age, gender, microsatellite instability (MSI) status, clinical stage, histological grade, tumor size, pT-stage, lymph node metastasis, distal metastasis, and cancer-specific survival (CSS) but was correlated with worse overall survival (OS: n � 536 patients) (P< 0.05). Furthermore, TCGA data demonstrated similar results, with no significant correlation between SOX2 and pathological characteristics. Further validation data (OS: n � 1408 and disease-free survival (DFS): n � 1367) showed that SOX2 expression was correlated with worse OS (HR � 1.35, 95% CI: 1.11–1.65, P � 0.004) and DFS (HR � 1.30, 95% CI: 1.04–1.62, P � 0.02). -e functional analyses showed that SOX2 involved in cell-cell junction, focal adhesion, extracellular matrix- (ECM-) receptor interaction, and MAP kinase activity. Our findings suggest that SOX2 expression may be correlated with the worse prognosis of CRC. renewal and multilineage differentiation and proliferation 1. Introduction potential, which are related to tumor progression, metas- Colorectal cancer (CRC) is one of the most common ma- tasis, recurrence, prognosis, and drug resistance [6–8]. Many lignant tumors and a major cause of cancer-related death in CSC-related markers have been identified and reported to be the world and in China [1, 2]. According to the GLOBOCAN associated with poor prognosis and resistance to therapy in estimates, approximately 1,800,977 new cases were diag- cancer [9, 10]. Sex-determining region Y-box 2 (SOX2), a nosed with CRC, leading to approximately 861,663 deaths high mobility group (HMG) DNA-binding domain, is due to this disease in 2018 worldwide [1]. Although some mapped to human chromosome 3q26.3–q27 and belongs to significant achievements have been made in early detection a key transcription factor [11]. SOX2 regulates the self-re- and treatment in recent years, most patients are diagnosed newal and pluripotency of undifferentiated stem cells such as with advanced disease and show a poor 5-year survival rate human embryonic stem cells and plays an important role in [3–5]. -erefore, it is needed to find new efficient bio- maintaining the stem cell–like features in cancer cells markers for the treatment of CRC along with the prognosis. [12–14]. Additionally, SOX2 involves in the migration, in- Cancer stem cells (CSCs) are a special subpopulation of vasion, and proliferation of cancer cells and resistance to tumor cells and have the ability and characteristics of self- therapy [15, 16]. SOX2 has been reported to be commonly 2 Journal of Oncology expressed in many human cancers, such as breast cancer, same institute were published. We mainly excluded review lung cancer, esophageal cancer, and CRC [17]. For example, articles, letters, conference abstracts, case reports, cell line/ animal studies, and articles lacking sufficient data. SOX2 expression is correlated with worse prognosis in breast cancer and gastric cancer [18, 19]. While SOX2 expression shows a favorable prognosis in non-small cell lung cancer 2.3. Data Extraction and Study Quality Assessment. -e and cervical cancer [20, 21]. -erefore, it is of great im- portance to determine the prognostic role of SOX2 ex- relevant data and search of the included studies were conducted from two independent authors (KS and JH) using pression in CRC. -e previous meta-analysis only included eight studies standardized forms, including the surname of the first au- thor, time of publication, country, ethnicity, median/mean with small sample sizes (n � 1113) and only analyzed the correlation between SOX2 and overall survival (OS) and a age, disease stage, antibody information, number of par- ticipants, cutoff values of SOX2, expression frequency, small part of the clinical features of CRC. Additionally, the clinicopathological parameters such as age, gender, micro- result on OS was not reasonable [22]. -erefore, the sig- satellite instability (MSI) status, clinical stage, histological nificance of SOX2 expression in CRC is not fully understood. grade, tumor size, pT-stage, lymph node metastasis, and For example, Lundberg et al. reported that SOX2 expression was not related to cancer-specific survival in CRC [23], but distal metastasis, and the survival data of multivariate Cox analysis such as cancer-specific survival (CSS), overall SOX2 expression was correlated with worse cancer-specific survival by Miller et al. [24]. -us, the current work with survival (OS), and disease-free survival (DFS). -e quality of the available publications was assessed according to the 3745 CRCs was performed to determine the survival impact of SOX2 expression on CRC ((cancer-specific survival (CSS), Newcastle–Ottawa Scale (NOS) for cohort studies [26, 27]. -ree parameters of quality included a total of nine scores: overall survival (OS), and disease-free survival (DFS)) and to evaluate the association between SOX2 expression and selection (0–4), comparability (0–2), and outcome assess- ment (0–3). In this meta-analysis, the publication with ≥6 general clinicopathological characteristics. scores was considered to be of high quality, and the NOS score with <6 was defined as low-quality study. Any dis- 2. Materials and Methods agreements in the selected literature were discussed by all authors and then reached a consensus. 2.1. Literature Search. -is meta-analysis was performed based on the Preferred Reporting Items for Systematic re- views and Meta-Analyses (PRISMA) statement [25] (Sup- 2.4. Validation Data from TCGA. -e RNA-sequencing data plementary Materials). -e electronic databases PubMed, and corresponding clinical information on CRC were ob- EMBASE, and Web of Science were comprehensively tained from -e Cancer Genome Atlas (TCGA) (https:// searched to identify eligible publications until July 29, 2019, portal.gdc.cancer.gov/repository). Eventually, 618 cases with by searching the following key words and search terms: CRC with sufficient expression data and clinical information “colorectal cancer OR colorectal tumor OR colorectal car- were selected. cinoma OR colorectal neoplasm OR CRC OR rectal cancer OR rectal tumor OR rectal carcinoma OR colon cancer OR colon tumor OR colon carcinoma” and “SOX2 OR SOX-2 2.5. Functional Analysis of SOX2. Association between SOX2 OR Sex-determining region Y-box protein 2 OR Sex de- and genes was analyzed using TCGA sequencing data. termining region Y box-2 OR Sex-determining region Y-box Spearman coefficients with an absolute value of >0.2 and 2 OR SRY box-2” (Supplementary Materials). Moreover, the P< 0.001 were applied for SOX2. -e potential function and reference lists of the identified articles were also examined to biological mechanism of the SOX2 gene such as GO (Gene find other relevant studies. Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were investigated by clusterProfiler package. 2.2. Eligibility Criteria. For the enrollment of publications, the main inclusion criteria were included as follows: (1) the patients with CRC were reported; (2) studies reported the 2.6. Survival Analysis from Validation Datasets. detection of SOX2 using immunohistochemistry (IHC); (3) Normalized GSE17538 (n � 232 patients), GSE39582 expression status of SOX2 was defined from the original (n � 558 patients), and TCGA (n � 618 patients) datasets articles; (4) studies provided available data to assess the were applied due to sufficient survival information and the correlation between SOX2 expression and clinicopatho- batch effects were adjusted using the ComBat method logical parameters; (5) studies provided sufficient hazard [28, 29]. Finally, 1408 CRC patients were used to further ratio (HR) with 95% confidence interval (CI) to evaluate the confirm whether SOX2 expression was still correlated with prognostic impact of SOX2 expression on CRC patients worse OS and 1367 CRC patients were used to further based on multivariate Cox survival analysis. If the results of validate whether SOX2 expression was still related to dis- interest were not completely reported, the corresponding ease-free survival (DFS). -e optimal cutoff value (SOX2: author will be contacted via e-mail. Only the recent article or 3.31) was selected and survival analysis was performed using the article with the most complete data was selected when “survival and survminer” packages. multiple articles using overlapping tissue samples from the Journal of Oncology 3 Records identified through Additional records identified database searching through other sources (n = 927) (n = 6) Records after duplicates removed (n = 513) Records excluded (n = 447): irrelevant title or abstract Records screened studies on cell lines or (n = 513) animals Full-text articles assessed Full-text articles excluded: for eligibility insufficient data based on (n = 66) the selection criteria (n = 53) Studies included in qualitative synthesis (n = 13) Studies included in quantitative synthesis (meta-analysis) (n = 13) Figure 1: Flow diagram of the study selection process. 2.7. Statistical Analysis. Data on meta-analysis were ob- For bioinformatics validation data, the TCGA patients were divided into positive and negative groups based on the tained from the original articles. -e pooled odds ratios (ORs) and the corresponding 95% CIs were calculated to median value of SOX2 expression. -e relationships between assess the relationship of SOX2 expression with the clini- SOX2 expression and the clinicopathological parameters copathological parameters. -e pooled HRs with their 95% were performed using the univariate logistic regression CIs were performed to estimate the prognostic impact of analysis. -e clinicopathological parameters included age, SOX2 expression on CRC patients using multivariate Cox MSI status, clinical stage, lymph node metastasis, distal survival analysis. As described in the report of IntHout et al., metastasis, venous invasion, and lymphatic invasion. the Hartung–Knapp–Sidik–Jonkman (HKSJ) method was Analysis for validation data was performed by using R applied to improve the reliability of the pooled results with version 3.5.1 [R Core Team, 2018]. ≤10 studies in the current meta-analysis [30]. -e hetero- geneity assumption between studies was measured using 3. Results Cochran’s Q statistic [31]. A Q test of P< 0.1 was considered to be a significant heterogeneity. When substantial het- 3.1. Study Characteristics. -e flow diagram for the study erogeneity was detected, sensitivity analyses were conducted selection is presented in Figure 1. Based on the selection to estimate the change of heterogeneity and stability of an criteria, inappropriate studies were excluded. Finally, 13 individual study on the recalculated results by removing a studies published between 2010 and 2019 were identified in single study [32]. -e possible publication bias was per- the present meta-analysis [6, 14, 23, 24, 34–42], including formed by Egger’s test [33]. -e pooled ORs and HRs were 2337 patients with CRC. Eligible studies were conducted in calculated using “metafor” package via R version 3.5.1 [R China, Korea, Singapore, Australia, Germany, Sweden, and Core Team, 2018]. Results of publication bias were carried -e Netherlands. Among these studies, expression of SOX2 out using Stata software (version 12.0, Stata Corporation, was evaluated by IHC. 10 studies with 1431 cases evaluated College Station, TX, US). -e code for the relevant examples the relationship between SOX2 expression and the clini- is listed in Supplementary Materials. copathological parameters [14, 23, 24, 35–41]. Five studies Screening Included Eligibility Identification 4 Journal of Oncology Table 1: Main characteristics of the eligible publications. Cutoff Cancer Clinical Survival- First author Country Age Stage Antibody Sources of antibody Staining values Total features MA (IHC) (E+ %) Clone 57CT23.3.4; Ong et al. Anti- 310 Singapore NA 1–4 Abcam, Cambridge, Cytoplasm 10% No CSS [42] SOX2 (NA) MA Clone D6D9, cell Neumann Anti- 114 Germany 66.5 NA Signaling technology, Nuclei 10% Yes NA et al. [41] SOX2 (21.1%) Danvers, MA Han et al. Anti- 44 China NA NA Epitomics NA NA Yes NA [40] SOX2 (20.5%) Anti- Abcam, Cambridge, 110 Lee et al. [39] Korea NA 1–4 Nuclei 5% Yes NA SOX2 UK (17.3%) Anti- Cell Signaling 67 Liu et al. [43] China NA 1–4 Nuclei ≥2 scores Yes NA SOX2 Technology, Inc (22.4%) Anti- ab75485, Abcam, 89 Ma et al. [38] China 65 1–4 NA >1.40 Yes NA SOX2 Cambridge, MA (50.6%) Raghoebir -e Anti- 135 NA NA Immune systems Nuclei 5% Yes NA et al. [37] Netherlands SOX2 (20.7%) Lundberg Anti- Abcam, Cambridge, 441 Sweden NA 1–4 Nuclei NA Yes CSS et al. [23] SOX2 UK (10.7%) Yan et al. Anti- 280 China 65 3–4 Abcam NA 2.5 Yes NA [36] SOX2 (41.8%) EPR3131; Abcam cell Miller et al. Anti- 104 Australia 66.7 3 Signaling Technology, Nuclei NA Yes CSS, OS [24] SOX2 (18.3%) Danvers Zheng et al. Anti- Mass cat. no. 636675, 47 China NA 1–4 NA NA Yes NA [35] SOX2 EMD Millipore (80.9%) Han et al. Anti- 164 Korea 59.8 3 Billerica, MA, USA NA ≥1 score No DFS [44] SOX2 (82.3%) Anti- 432 Li et al. [34] China NA 1–4 #ab92494 NA NA No OS SOX2 (NA) NA: not applicable; IHC: immunohistochemistry; E+: positive/high expression; MA: multivariate Cox analysis; DFS: disease-free survival; OS: overall survival; CSS: cancer-specific survival. Table 2: Summary of results from this meta-analysis. Variables OR [95% CI] Heterogeneity (p) t value P value Studies Cases Age (≥60 vs.< 60 years) 0.80 [0.13, 4.77] 0.618 − 1.621 0.352 2 530 Gender (male vs. female) 0.91 [0.51, 1.64] 0.138 − 0.439 0.684 5 991 MSI status (MSI vs. MSS) 1.40 [0.66, 3.00] 0.513 1.422 0.25 4 775 Clinical stage (stages 3-4 vs. 1-2) 1.34 [0.32, 5.64] 0.028 0.647 0.564 4 619 Histological grade (grades 3-4 vs. 1-2) 1.65 [0.62, 4.33] 0.004 1.428 0.227 5 999 Tumor size (≥5 vs. ≤5 cm) 0.78 [0.00, 1913.29] 0.018 − 0.398 0.759 2 347 pT-stage (T 3-4 vs. 1-2) 1.12 [0.36, 3.43] 0.065 0.308 0.778 4 526 Lymph node metastasis (yes vs. no) 3.19 [0.58, 17.66] 0.368 2.916 0.1 3 225 Distal metastasis (yes vs. no) 1.26 [0.14, 10.91] 0.015 0.454 0.694 3 438 OR: odds ratio; CI: confidence interval; MSI: microsatellite instability; MSS: microsatellite stability. with 1451 cases assessed the association between SOX2 OR � 0.80, P � 0.352), gender (five studies with 991 cases, expression and the prognosis using multivariate Cox sur- male vs. female: OR � 0.91, P � 0.684), MSI status (four vival analysis [6, 23, 24, 34, 42]. 13 studies were considered to studies with 775 cases, MSI vs. microsatellite stability (MSS): be of high quality by using NOS. -e details of the included OR � 1.40, P � 0.25) (Figure 2). studies are summarized in Table 1 and Table S1. No correlation was found between SOX2 expression and clinical stage (four studies with 619 cases, stages 3-4 vs. 1-2: OR � 1.34, P � 0.564) and histological grade (five studies with 3.2. Correlation of SOX2 Expression with Clinicopathological 999 cases, grades 3-4 vs. 1-2: OR � 1.65, P � 0.227) (Figure 3). Variables. A summary of the calculated results is shown in No relationship was observed between SOX2 expression Table 2. No association was found between SOX2 expression and tumor size (two studies with 347 cases, ≥5 vs. ≤5 cm: and age (two studies with 530 cases, ≥60 vs. <60 years: OR � 0.78, P � 0.759), pT-stage (four studies with 526 cases, Journal of Oncology 5 Studies (age) Studies (gender) OR [95% CI] OR [95% CI] Neumann et al. [41] 1.82 [0.72, 4.59] Ma et al. [38] 0.94 [0.40, 2.23] Liu et al. [43] 1.72 [0.48, 6.14] Ma et al. [38] 1.27 [0.52, 3.05] Lundberg et al. [23] 0.71 [0.34, 1.46] Lundberg et al. [23] 0.51 [0.28, 0.95] Yan et al. [36] 0.89 [0.55, 1.43] FE model 0.80 [0.13, 4.77] FE model 0.91 [0.51, 1.64] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (a) (b) Studies (MSI) OR [95% CI] Lee et al. [39] 1.71 [0.42, 7.01] Raghoebir et al. [37] 0.88 [0.27, 2.87] Lundberg et al. [23] 1.16 [0.51, 2.61] Miller et al. [24] 2.81 [0.89, 8.81] FE model 1.40 [0.66, 3.00] 0.05 0.25 1 4 Odds ratio (log scale) (c) Figure 2: Forest plot for the correlation between SOX2 and age, gender, and MSI status. (a) Age (≥60 vs. <60 years); (b) gender (male vs. female); (c) MSI status (MSI vs. MSS). OR: odds ratio; CI: confidence interval; MSS: microsatellite stability; MSI: microsatellite instability. pT-stages 3-4 vs. 1-2: OR � 1.12, P � 0.778), lymph node was significantly correlated with the histological grade metastasis (three studies with 225 cases, yes vs. no: (OR � 2.70, 95% CI � 1.15–6.37, P � 0.035), with no het- OR � 3.19, P � 0.1), and distal metastasis (three studies with erogeneity (P � 0.250). 438 cases, yes vs. no: OR � 1.26, P � 0.694) (Figure 3). 3.5. Publication Bias. No publication bias was found be- 3.3. Survival Impact of SOX2 Expression Using Multivariate tween SOX2 expression and gender and histological grade Cox Analysis. Data showed that SOX2 expression was not (P> 0.1) (Figure S1). correlated with cancer-specific survival (CSS) of CRC in three studies with 855 patients (HR � 1.18, P � 0.667) (Figure 4) but was correlated with worse overall survival 3.6. TCGA. Six hundred eighteen cases with CRC were (OS) in two studies with 536 patients (P< 0.05) [24, 34]. enrolled from TCGA. As shown in Table 3, the results using univariate logistic regression analysis showed that SOX2 3.4. Heterogeneity Analysis. Heterogeneity analysis was expression was not significantly associated with age (≥60 vs.<60 years: OR � 1.03, 95% CI � 0.73–1.46, P � 0.859), MSI conducted between SOX2 expression and clinical stage, histological grade, and pT-stage. We conducted sensitivity status (MSI vs. MSS : OR � 1.08, 95% CI � 0.77–1.52, P � 0.663), clinical stage (stages 3-4 vs. 1-2: OR � 1.37, 95% analyses to estimate the change of the pooled results. When the study of Lundberg et al. [23] was deleted, the recalculated CI � 0.99–1.89, P � 0.059), venous invasion (yes vs. no: OR was still not correlated with the clinical stage (OR � 0.55, OR � 1.12, 95% CI � 0.75–1.65, P � 0.585), lymphatic inva- 95% CI � 0.06–4.66, P � 0.350), with no evidence of het- sion (yes vs. no: OR � 1.27, 95% CI � 0.91–1.79, P � 0.162), erogeneity (P � 0.272). When the study of Han et al. [40] lymph node metastasis (yes vs. no: OR � 1.37, 95% was omitted, the recalculated result was still not associated CI � 0.99–1.88, P � 0.057), and distal metastasis (yes vs. no: with the pT-stage (OR � 1.04, 95% CI � 0.30–3.54, OR � 1.13, 95% CI � 0.72–1.79, P � 0.597), but SOX2 ex- P � 0.908), with no heterogeneity (P � 0.216). When the pression was correlated with gender (male vs. female: study of Yan et al. [36] was removed, the recalculated result OR � 0.69, 95% CI � 0.5–0.94, P � 0.02). 6 Journal of Oncology Studies (clinical stage) OR [95% CI] Studies (tumor grade) OR [95% CI] Neumann et al. [41] 1.70 [0.64, 4.50] Lundberg et al. [23] 2.18 [1.16, 4.11] Liu et al. [43] 2.00 [0.60, 6.70] Liu et al. [43] 1.02 [0.32, 3.23] Yan et al. [36] 0.80 [0.46, 1.38] Ma et al. [38] 0.28 [0.07, 1.17] Lundberg et al. [23] 2.57 [1.34, 4.96] Zheng et al. [35] 0.16 [0.01, 3.08] Miller et al. [24] 7.04 [2.37, 20.93] FE model 1.34 [0.32, 5.64] FE model 1.65 [0.62, 4.33] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (a) (b) Studies (pT-stage) OR [95% CI] Studies (N status) OR [95% CI] Han et al. [40] 22.45 [1.21, 415.67] Neumann et al. [41] 4.15 [1.43, 12.09] Neumann et al. [41] 7.80 [0.45, 136.63] Han et al. [40] 7.56 [0.85, 66.97] Ma et al. [38] 1.72 [0.56, 5.33] Liu et al. [43] 1.53 [0.40, 5.81] Yan et al. [36] 0.88 [0.54, 1.46] FE model 3.19 [0.58, 17.66] FE model 1.12 [0.36, 3.43] 0.05 0.25 1 4 0.05 0.25 1 4 Odds ratio (log scale) Odds ratio (log scale) (c) (d) Studies (M status) OR [95% CI] Neumann et al. [41] 3.04 [1.15, 8.04] Han et al. [40] 5.25 [0.95, 29.05] Yan et al. [36] 0.78 [0.44, 1.39] FE model 1.26 [0.14, 10.91] 0.05 0.25 1 4 Odds ratio (log scale) (e) Figure 3: Forest plot for the correlation between SOX2 and clinical stage, histological grade, pT-stage, lymph node metastasis, and distal metastasis. (a) Clinical stage: stages 3-4 vs. 1-2; (b) tumor grade: grades 3-4 vs. 1-2; (c) pT-stage: T 3-4 vs. 1-2; (d) lymph node metastasis (N status): yes vs. no; (e) distal metastasis (M status): yes vs. no. OR: odds ratio; CI: confidence interval. 3.7. SOX2 Involves in Some Key Molecular Functions in CRC. these pathways are closely associated with cancer GO and KEGG analyses showed that SOX2 involved in cell- development. cell junction, focal adhesion, extracellular matrix- (ECM-) receptor interaction, transmembrane receptor protein ty- 3.8. Further Survival Analysis from Validation Data. -e rosine kinase activity, transmembrane-ephrin receptor ac- tivity, semaphorin receptor activity, MAP kinase activity, validation data included 1408 patients with CRC, and the result also confirmed that SOX2 expression was significantly mitogen-activated protein kinase binding, transmembrane associated with worse OS (HR � 1.35, 95% CI: 1.11–1.65, receptor protein kinase activity, etc. in CRC (Figure 5), and Journal of Oncology 7 Studies HR [95% CI] Ong et al. [42] 1.03 [0.72, 1.48] Lundberg et al. [23] 1.04 [0.65, 1.67] Miller et al. [24] 6.19 [2.24, 17.10] FE model 1.18 [0.28, 4.89] 0.05 0.25 1 4 Observed outcome Figure 4: Forest plot for the correlation between SOX2 and cancer patients’ prognosis using multivariate cox analysis in cancer-specific survival (CSS). HR: hazard ratio; CI: confidence interval. Table 3: Correlation of SOX2 with the clinicopathological characteristics from the cancer genome atlas. Variables Comparison OR with 95% CI P Cases Age ≥60 vs. <60 years 1.03 (0.73–1.46) 0.859 618 Gender Male vs. female 0.69 (0.5–0.94) 0.02 618 MSI status MSI vs. MSS 1.08 (0.77–1.52) 0.663 618 Clinical stage Stages 3-4 vs. 1-2 1.37 (0.99–1.89) 0.059 598 Venous invasion Yes vs. no 1.12 (0.75–1.65) 0.585 536 Lymphatic invasion Yes vs. no 1.27 (0.91–1.79) 0.162 557 Lymph node metastasis Yes vs. no 1.37 (0.99–1.88) 0.057 615 Distal metastasis Yes vs. no 1.13 (0.72–1.79) 0.597 545 OR: odds ratio; CI: confidence interval; MSI: microsatellite instability; MSS: microsatellite stability. P � 0.004) (Figure 6(a)). Further validation data with 1367 impact in patients with CRC are still largely uncertain. In the CRC patients were used, and the result showed that SOX2 present work, we determined the clinicopathological effect of SOX2 and its expression on the prognostic impact of expression was associated with worse DFS (HR � 1.30, 95% CI: 1.04–1.62, P � 0.02) (Figure 6(b)). patients with CRC. -e relationships between SOX2 expression and the clinicopathological characteristics of CRC were investigated. 4. Discussion -e pooled data showed that SOX2 expression was not CSCs contribute to tumor metastasis and prognosis and correlated with age and MSI status, which were consistent with the previous studies on age [23, 38] and MSI status therapeutic resistance [45, 46]. CSCs may offer new promising therapeutic targets of treatment modalities ap- [23, 24, 37, 39]. Further TCGA also showed no correlation plicable to human various cancers [47, 48]. SOX2 involves in with age and MSI status. Although no correlation was found the development and maintenance of stem-like properties in between SOX2 expression and gender among all eligible cancer cells [14, 15]. SOX2 involves in many signaling studies, a large population with 441 cases reported that SOX2 expression was negatively correlated with gender and was pathways such as VEGF, MAPK, Notch, P53, Wnt, and Jak- STAT, regulates many expression of genes, and regulates lower in males than in females [23]. Further data from TCGA also demonstrated a negative association with gen- self-renewal and differentiation of stem cells, which may contribute to migration, invasion, and proliferation of der, suggesting that more studies with larger sample sizes are needed to confirm this controversial finding. SOX2 ex- cancer cells and the stemness of cancer stem cells, thereby affecting cancer progression, prognosis, and resistance to- pression was not associated with clinical stage, histological ward anticancer therapies [14, 15, 17]. SOX2 expression is grade, tumor size, pT-stage, lymph node metastasis, and found across a wide range of human cancers such as breast distal metastasis, which were in line with the previous cancer, lung cancer, and esophageal cancer [17]. SOX2 publications regarding clinical stage [14, 35, 38], histological grade [14, 36, 41], tumor size [36], pT-stage [36, 38, 41], expression is correlated with the prognosis of some human cancers such as non-small cell lung cancer and cervical lymph node metastasis [14, 40], and distal metastasis [36]. Moreover, TCGA data also confirmed no significant asso- cancer with better prognosis [20, 21] and breast cancer and gastric cancer with worse prognosis [18, 19]. Studies have ciation with clinical stage, lymph node metastasis, and distal metastasis. -ese results suggested that SOX2 expression reported that SOX2 is frequently expression in CRC [6, 34, 35]. However, the function of SOX2 and its survival was not significantly associated with progression and BP CC MF 8 Journal of Oncology p.adjust p.adjust 6e − 06 Axon development Axonogenesis Positive regulation of nervous system development 7e − 06 Synapse organization Axon guidance 8e − 06 Neuron projection guidance Heart contraction Heart process 0.01 9e −06 Regulation of heart contraction Gliogenesis 1e − 05 Neuronal cell body 0 5 101520 Postsynapse Actin cytoskeleton 0.02 Cell-cell junction Axon part Receptor complex Contractile fiber part Contractile fiber Site of polarized growth Sarcolemma 0.03 Actin binding Sulfur compound binding Actin filament binding Structural constituent of cytoskeleton Transmembrane receptor protein tyrosine kinase activity Transmembrane receptor protein kinase activity 0.04 Mitogen-activated protein kinase kinase binding Map kinase kinase kinase activity Semaphorin receptor activity Transmembrane-ephrin receptor activity 0.025 0.050 0.075 0.100 Generatio Count 10 30 20 40 (a) (b) Figure 5: SOX2 involves in some cancer mechanisms, (a) GO (gene ontology) analysis; (b) KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. metastasis of CRC. Further relevant studies are necessary to the main ethnic population was Asian and European; other confirm our results in the future. ethnic groups, such as Africans, were lacking. -ird, due to -e survival impact of SOX2 expression in patients with fewer studies, subgroups were insufficient and meta-re- CRC was performed based on multivariate Cox analysis. gression analysis was not performed. However, heteroge- SOX2 expression was not correlated with CSS but was neity analysis was carried out based on sensitivity analysis significantly associated with worse OS in CRC. Additionally, and the detailed reasons for the potential heterogeneity were further validation data from TCGA and GEO datasets (OS: not very certain. -e possible use of the inappropriate and n � 1408 CRC patients and DFS: 1367 CRC patients) different conditions of IHC methods such as different/un- clear cutoff values of SOX2 expression and different sources demonstrated that SOX2 expression was significantly cor- related with worse OS (HR � 1.35, P � 0.004) and DFS of anti-SOX2 antibody may lead to the potential sources of (HR � 1.30, P � 0.02). -ese analyses suggested that SOX2 heterogeneity. For example, in the future, the expression of was an independent prognostic marker for predicting poor SOX2 is defined as positive or negative, which should be prognosis. Additionally, the functional analysis showed that recommended using a uniform standard. Fourth, only Han SOX2 involved in cell-cell junction, focal adhesion, extra- et al. reported that SOX2 expression was correlated with DFS cellular matrix- (ECM-) receptor interaction, transmem- in 164 CRC cases (HR � 2.558, P � 0.020) [6]. Finally, brane receptor protein tyrosine kinase activity, sample sizes on the analyses between SOX2 expression and transmembrane-ephrin receptor activity, semaphorin re- the clinicopathological features and the prognosis were ceptor activity, mitogen− activated protein kinase binding, relatively small in the meta-analysis, more studies with large transmembrane receptor protein kinase activity, MAP ki- study population are necessary to further determine whether nase activity, etc., which further suggested that SOX2 may be SOX2 is correlated with clinical and prognostic value in CRC closely linked with CRC prognosis. based on IHC methods. -ere are several limitations in the present study. First, In conclusion, the current study suggested that SOX2 this meta-analysis has not been registered online. Second, expression was not significantly correlated with age, gender, ECM− receptor Focal interaction adhesion Journal of Oncology 9 1.00 SOX2 (P = 0.020) 1.0 0.75 0.8 0.50 0.6 0.4 P = 0.004 0.25 Hazard ratio = 1.35 Hazard ratio = 1.30 95% CI: 1.11 − 1.65 0.2 95% CI: 1.04 – 1.62 0.00 0.0 0 50 100 150 200 0 50 100 150 200 Time Time (months) SOX2 High (n = 839) High (859) Low (n = 528) Low (549) (a) (b) Figure 6: Survival analysis of SOX2 expression from validation data. (a) Overall survival (OS) in 1408 patients; (b) disease-free survival (DFS) in 1367 patients. MSI status, clinical stage, histological grade, tumor size, pT- Acknowledgments stage, lymph node metastasis, distal metastasis, and CSS but -e authors gratefully acknowledge -e Cancer Genome was associated with worse OS and DFS. 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Journal of Oncology – Hindawi Publishing Corporation

Published: Feb 13, 2020

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