The prognostic value of the mir-200 family in ovarian cancer: a meta-analysis

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1 AOGS REVIEW ARTICLE The prognostic value of the mir-200 family in ovarian cancer: a meta-analysis CAN SHI & ZHENYU ZHANG Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Key words Meta-analysis, mir-200, ovarian cancer, survival Correspondence Zhenyu Zhang, Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti SouthRoad, Chaoyang District, Beijing , China zhenyuzhang64@163.com Conflict of interest All authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Shi C, Zhang Z. The prognostic value of the mir-200 family in ovarian cancer: a meta-analysis. Acta Obstet Gynecol Scand 2016; 95: Received: 3 November 2015 Accepted: 25 January 2016 DOI: /aogs Abstract Introduction. To assess the association between mir-200 family expression and overall survival/progression-free survival in women with ovarian cancer. Material and methods. A systematic literature search, up to September 2015, in PubMed, EMBASE and Cochrane Library was performed to identify articles that assessed the association between mir-200 family expression and the survival of women with ovarian cancer. Summary hazard ratios and 95% confidence interval were calculated to estimate the effect. Results. A total of seven articles, consisting of 553 women, were included in this meta-analysis. Overall, significantly improved overall survival/progression-free survival were observed with higher expression of the mir-200 family in women with ovarian cancer (overall survival, hazard ratio = 0.34, 95% confidence interval ; progression-free survival, hazard ratio = 0.64, 95% confidence interval ). Subgroup analysis revealed that there was a significant association between enhanced expression of the mir-200c and improved overall survival (hazard ratio = 0.20, 95% confidence interval ) and progression-free survival (hazard ratio = 0.30, 95% confidence interval ). Moreover, in the Asian population, a significant association was found between higher expression of the mir-200 family and improved overall survival (hazard ratio = 0.20, 95% confidence interval ). Conclusion. High expression of mir-200c may predict improved survival in women with ovarian cancer and high expression of the mir-200 family significantly improves overall survival for Asian women. Abbreviations: HRs, hazard ratios; mirna, microrna; OR, overall survival; PFS, progression-free survival. Introduction Ovarian cancer represents the second most common gynecological malignancy (after cervical cancer) and accounts for over half of all deaths among women with gynecological neoplasms (1). The prognosis of ovarian cancer is proven to strongly depend on the disease stage at the time of diagnosis: the 5-year survival rate for patients with stage I disease (ovary confined) is 90% and this rate dramatically decreases to around 20% for those with advanced stages (stage III IV) (2). Given the poor survival of women with ovarian cancer, there is a pressing clinical demand to search for prognostic biomarkers for effectively evaluating the outcomes of this disease. MicroRNAs (mirnas), a class of small non-coding RNAs that control gene expression by targeting messenger RNA, are proposed as promising diagnostic and prognostic markers for various cancers (3 8), including ovarian Key Message Enhanced expression of mir-200c significantly improved survival outcome of ovarian cancer patients, especially those from Asia. ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

2 mir-200 family in ovarian cancer C. Shi & Z. Zhang cancer. mir-200, a family of tumor suppressor mirnas consisting of mir-141, mir-200a, mir-200b, mir-200c and mir-429, is significantly involved in the inhibition of epithelial-to-mesenchymal transition, repression of cancer stem cell self-renewal and differentiation, modulation of cell division and apoptosis, and reversal of chemoresistance (9). The related pathway of mir-141, mir-200a, mir-200b, mir-200c and mir-429 is mir- NAs in cancer. A study suggests that multiple mirnas of mir-200 family work together to prevent cancer cell metastasis by inhibiting the expression of involved key genes in the process (10). Hence, the mir-200 family mirnas may act as master regulators in ovarian cancer by targeting some cancer-related genes (10). In addition, Leskel a et al. suggested that the mir-200 family might be serving as a prognostic factor and a marker for treatment failure in ovarian cancer (11). Over the past few years, accumulating data appeared to verify the prognostic implications of the mir-200 family in women with ovarian cancer (10 15). Definitive conclusions, however, have not been drawn because of the limited sample size and inconsistent results across these studies. Therefore, it is necessary to evaluate the association of the mir-200 family expression with the survival of women with ovarian cancer by a metaanalysis. In our present study, we systematically searched the relevant articles and performed a meta-analysis to better evaluate the association between expression of the mir- 200 family and the survival of women with ovarian cancer. Material and methods A systematic literature search in PubMed, EMBASE and Cochrane Library was performed to identify articles that assessed the association between mir-200 family expression and the survival of women with ovarian cancer up to September The following terms: ( mir-200a OR mir-200b OR mir-200c OR mir-141 OR mir-429 ) AND ( ovarian cancer OR ovarian carcinoma ) AND ( prognosis OR survival ) were used for the search without language restriction. The reference lists of eligible articles were also screened for additional articles. Studies were included if they: (i) evaluated the association between mir-200 family expression and overall survival (OS)/progression-free survival (PFS) in patients with ovarian cancer; and (ii) provided sufficient information to calculate hazard ratios (HRs) and their 95% CIs. For studies with multiple publications focused on the same study population or studies with duplicate results published in different journals, we included only the most recent and complete study. Reviews, reports, letters, comments and studies that did not provide sufficient data were excluded. With a pre-designed form (Table 1), two investigators (CS and ZZ) independently extracted the following data from each study: first author, publication year, study location, number of patients, types of mirna, and HR, LCI (lower confidence interval) and UCI (upper confidence interval) of OS and PFS. Any discrepancies were resolved by discussion. Quality of included studies was Table 1. Characteristics of studies included in the meta-analysis. Study Year Sample size Country RNA HR (OS) LCI (OS) UCI (OS) HR (PFS) LCI (PFS) UCI (PFS) Type of data Cao China mir-200a High vs. Low Cao China mir-200b High vs. Low Cao China mir-200c High vs. Low Gao China mir-200c High vs. Low Gao China mir High vs. Low Leskel a Spain mir Continuous Leskel a Spain mir-200a Continuous Leskel a Spain mir-200b Continuous Leskel a Spain mir-200c Continuous Leskel a Spain mir Continuous Marchini Italy mir-200b High vs. Low Marchini Italy mir-200c High vs. Low Marchini Italy mir-200c High vs. Low Hu USA mir-200a High vs. Low Mateescu France mir-200a/ High vs. Low Sun China mir-200a High vs. Low HR, hazard ratio; LCI, lower confidence interval; UCI, upper confidence interval; OS, overall survival; PFS, progression-free survival. High vs. Low, high mirna expression versus low mirna expression. Continuous, continuous data of mirna expression. 506 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

3 C. Shi & Z. Zhang mir-200 family in ovarian cancer assessed using the Newcastle Ottawa Scale (16) ( which is a validated technique for assessing the quality of observational and non-randomized studies. The scale uses a star system based on three criteria: participant selection, comparability of study groups and assessment of outcome or exposure. There were nine stars in total, one star for each item, except for the item Comparability of cohorts on the basis of the design or analysis, which possesses two stars. We have followed the PRISMA guidelines to report this meta-analysis. Statistical analysis Summary HRs and 95% CIs were calculated by using a random effects model (inverse-variance method) to assess the prognostic value of mir-200 family expression for the survival of women with ovarian cancer. The heterogeneity across studies was examined using Cochran s Q Figure 1. Flow diagram indicating the process of study selection for meta-analysis. statistic and the I 2 statistic (17). Subgroup analyses stratified by study location and the mir-200 family members (mir-200a, mir-200b and mir-200c) were conducted. Publication bias was assessed by Egger s test (18). Data analyses were performed with STATA 12.0 version software (19). A p-value <0.05 was considered statistically significant. One study at a time was trimmed to assess the sensitivity of the meta-analysis. The pooled results before and after the trim were compared and a reversed difference after the trim indicated unstable results. Results Figure 1 shows the process of study selection. According to the search strategy, a total of 79 articles were initially retrieved. After trimming the duplicate literature (n = 28), unrelated studies (n =31), and summaries, letters and conference excerpts (n = 5), 15 studies remained for further screening of the full-text. After eliminating eight articles without required data, seven studies were included in this meta-analysis (10 15,20). These eligible studies consisted of 16 sets of data with 553 women. Detailed characteristics of the included studies are presented in Table 1. As indicated by the result of the quality assessment, all the included studies have relatively high quality with six to nine stars (Table 2). The results of pooled analysis are shown in Table 3. Overall, significantly improved OS/PFS were observed with higher expression of the mir-200 family in women with ovarian cancer (OS, HR = 0.34, 95% CI ; PFS, HR = 0.64, 95% CI , Figure 2). Stratified analysis by mir-200 family member types revealed that there was a significant association between enhanced expression of mir-200c and improved OS (HR = 0.20, 95% CI ) and PFS (HR = 0.30, 95% CI , Figure 3), but there was no significant association with respect to mir-200a or mir-200b. Moreover, a Table 2. Methodological quality of studies included in the meta-analysis. Study Cao Gao Leskel a Marchini Hu Mateescu Sun Representativeness of the exposed cohort Selection of the non-exposed cohort Ascertainment of exposure Demonstration that outcome of interest was not present at start of study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow up long enough for outcomes to occur Adequacy of follow up of cohorts Stars ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

4 mir-200 family in ovarian cancer C. Shi & Z. Zhang Table 3. Results of quantitative analysis. Subgroup HR 95% CI I 2 (%) P H OS Overall Member type mir-200a mir-200b mir-200c Location Asia Europe PFS Overall Member type mir-200a mir-200b mir-200c HR, hazard ratio; OS, overall survival; PFS, progression free survival; P H,P heterogeneity. significant association was found between higher expression of the mir-200 family and improved OS in the Asian population (HR = 0.20, 95% CI , Figure 4), compared with the European population. The results of the heterogeneity test are shown in Table 3. There was significant heterogeneity across studies for the pooled analysis of the mir-200 family and OS (I 2 = 66.1%, p = 0.001), which might be caused by the studies involving mir-200b (I 2 = 91.2%, p = 0.001), because there was no significant heterogeneity across the studies involving mir-200a and mir-200c. Nor was significant heterogeneity found in the subgroup analysis of the studies of the European population. No significant heterogeneity existed across studies regarding mir-200 and PFS (I 2 = 44.0%, p = 0.065). As indicated by Egger s test, there was no significant publication bias for both OS (Egger s test, p = 0.097) and PFS (Egger s test, p = 0.234). (a) (b) Figure 2. Forest plots for the association between mir-200 expression and overall survival (a) progression-free survival (b) of patients with ovarian cancer. 508 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

5 C. Shi & Z. Zhang mir-200 family in ovarian cancer (a) (b) Figure 3. Forest plots of subgroup analysis regarding specific mir-200 family member expression and overall survival (a) and progression-free survival (b) of patients with ovarian cancer. Sensitivity analyses of OS and PFS were performed. After trimming one study at a time, the pooled results did not reverse, indicating that the results of this metaanalysis were stable (Figure 5). Discussion In the current study, we assessed the association between mir-200 family expression and the survival of women with ovarian cancer. The pooled analysis of seven studies (16 sets of data with 553 women) demonstrated that higher expression of the mir-200 family significantly improved the OS and PFS in women with ovarian cancer. However, the subgroup analysis of mir-200 family members revealed that the improved OS and PFS existed only for enhanced expression of mir-200c. Moreover, a significant association between the expression of three mir-200 family members (mir-200a, mir- 200b and mir-200c) and favorable OS was observed in the Asian population. ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

6 mir-200 family in ovarian cancer C. Shi & Z. Zhang Figure 4. Forest plots of subgroup analysis by study location regarding the mir-200 family expression and overall survival of patients with ovarian cancer. (a) (b) Figure 5. Sensitivity analyses of studies regarding the overall survival (a) and progression free survival (b). It has been shown that mir-200s are accumulated in ovarian cancer (21 23). Expression of mir-200a, mir- 200b and mir-200c was significantly higher in ovarian cancer tissues than in normal ovarian epithelial tissues, and enhanced expression of these three members was significantly associated with poor OS (12). Furthermore, loss of mir-200c is parallel with increased expression of vascular endothelial growth factor A, which is targeted by mir-200c and relates to OS and PFS in multivariate analysis (13). In addition, Nam et al. suggested that overexpression of mir-200 family members was significantly associated with poor OS in women with ovarian cancer (24). Moreover, some studies indicated that high expression of mir-200s was associated with a favorable prognosis (10,21,25), and downregulation of mir-200s was related with relapse of ovarian cancer (13). Besides, the study of Hu et al. (10) indicated that low-level expression of three mir-200 family members (mir-200a, mir-200b and mir-429) was significantly associated with poor OS. The opposite results existed for mir-200b in the study of Marchini et al. (13), which might be caused by the different methods (mirna microarrays versus real-time RT- PCR) used for mirna detection and the samples (frozen tissue versus formalin-fixed, paraffin-embedded tissues) from other studies. Although the inconsistent results reported in these studies had not yet been interpreted comprehensively, part of the discrepancy might be attributed to the difference in microarray platforms since these mirna profiling studies were performed with different microarray 510 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

7 C. Shi & Z. Zhang mir-200 family in ovarian cancer platforms. Besides, differences in experimental design across studies could also affect the interpretation of results. Notably, the insufficient number of tumor samples in the included studies could result in limited statistical power of the prognostic value of the mir-200 family. To our knowledge, this is the first meta-analysis to pool available data to evaluate the prognostic value of the mir-200 family in ovarian cancer. Our results of the meta-analysis are in line with most of the former researches and suggest that high expression of mir-200c may predict improved survival in women with ovarian cancer, and high expression of the mir-200 family significantly improves OS for Asian women. The protective effect of the mir-200 family for women with ovarian cancer found in our study might be explained by the potential suppressor role of mir-200 on malignant tumors by targeting ZEB1 and ZEB2 (members of the zinc-finger E- box binding homeobox family) (26 28). In addition, mir-200 could inhibit cancer stem cell self-renewal and differentiation, modulate cell division and apoptosis, and reverse chemoresistance (9). Moreover, it is proposed that specific members of the mir-200 family might be more important for prognosis of ovarian cancer (11). Hence, women would be benefited from a better understanding of the mir-200 family with regard to tumor suppressor roles of the mir-200 family in human cancer. Some limitations in our meta-analysis have to be acknowledged. First, pooled HR was calculated on the basis of 16 studies with a small sample size of 553 women. Second, significant heterogeneity was found across studies regarding the association of the mir-200 family with OS. Subgroup analysis showed that the main source of heterogeneity might result from studies on mir-200b. The inconsistent definition of OS/PFS, different types of disease, various sources of the sample and different methods/platforms for mrna detection might also introduce heterogeneity to this meta-analysis. Although a random effects model was used, we did not find the exact source of the heterogeneity. Third, this meta-analysis did not evaluate the prognostic value of a combination of mir-200 and other mirna markers for ovarian cancer. Conclusion This meta-analysis indicated that high expression of mir-200c may predict improved survival in women with ovarian cancer and high expression of the mir-200 family significantly improves OS for the Asian population. A comprehensive understanding of the tumor suppressor roles of the mir-200 family in ovarian cancer remains to be elucidated. Funding No specific funding. References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, CA Cancer J Clin. 2014;64: Chan JK, Cheung MK, Husain A, Teng NN, West D, Whittemore AS, et al. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol. 2006;108: Cho W. MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol. 2010;42: Oom AL, Humphries BA, Yang C. MicroRNAs: novel players in cancer diagnosis and therapies. Biomed Res Int. 2014;2014: Di Leva G, Croce CM. The role of micrornas in the tumorigenesis of ovarian cancer. Front Oncol. 2013;3: Cheng G. Circulating mirnas: roles in cancer diagnosis, prognosis and therapy. Adv Drug Deliv Rev. 2015;81: Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67: Davidson B, Trope CG, Reich R. The clinical and diagnostic role of micrornas in ovarian carcinoma. Gynecol Oncol. 2014;133: Feng X, Wang Z, Fillmore R, Xi Y. MiR-200, a new star mirna in human cancer. Cancer Lett. 2014;344: Hu X, Macdonald DM, Huettner PC, Feng Z, El Naqa IM, Schwarz JK, et al. A mir-200 microrna cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol. 2009;114: Leskel a S, Leandro-Garcıa LJ, Mendiola M, Barriuso J, Inglada-Perez L, Mu~noz I, et al. The mir-200 family controls b-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer. 2011;18: Cao Q, Lu K, Dai S, Hu Y, Fan W. Clinicopathological and prognostic implications of the mir-200 family in patients with epithelial ovarian cancer. Int J Clin Exp Pathol. 2014;7: Marchini S, Cavalieri D, Fruscio R, Calura E, Garavaglia D, Nerini IF, et al. Association between mir-200c and the survival of patients with stage I epithelial ovarian cancer: a retrospective study of two independent tumour tissue collections. Lancet Oncol. 2011;12: Mateescu B, Batista L, Cardon M, Gruosso T, De Feraudy Y, Mariani O, et al. mir-141 and mir-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 2011;17: ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

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