microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6

Xiao,Fenqiang; Zhang,Wu; Zhou,Lin; Xie,Haiyang; Xing,Chunyang; Ding,Songming; Chen,Kangjie; Zheng,Shusen

doi:10.3892/or.2013.2715

microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6

Authors:
- Fenqiang Xiao
- Wu Zhang
- Lin Zhou
- Haiyang Xie
- Chunyang Xing
- Songming Ding
- Kangjie Chen
- Shusen Zheng
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Affiliations: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, P.R. China, Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
Published online on: September 4, 2013 https://doi.org/10.3892/or.2013.2715
Pages: 2203-2210

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Abstract

Deregulation of microRNA‑200a (miR‑200a) has been observed in different types of diseases, including cancers. However, the exact roles of miR‑200a in hepatocellular carcinoma (HCC) are still largely unknown. We aimed to elucidate the prognostic implications of miR‑200a and its biological function in HCC. Quantitative polymerase chain reaction was used to evaluate miR‑200a expression. Western blotting was performed to evaluate the protein level. Gain-of-function studies were performed to evaluate the roles of miR‑200a in HCC. Our results revealed that miR‑200a was frequently downregulated in HCC. In addition, multivariate analysis confirmed that miR‑200a was significantly associated with the overall survival of HCC patients. In vitro assays demonstrated that miR‑200a suppressed the proliferation of HCC cells by induction of G1 phase arrest. Furthermore, CDK6 was identified as a novel functional target of miR‑200a. Our data indicate that miR‑200a functions as a potential tumor suppressor in HCC.

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1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
2	Aravalli RN, Steer CJ and Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology. 48:2047–2063. 2008. View Article : Google Scholar
3	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
4	Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar
5	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Schratt GM, Tuebing F, Nigh EA, et al: A brain-specific microRNA regulates dendritic spine development. Nature. 439:283–289. 2006. View Article : Google Scholar : PubMed/NCBI
8	Brennecke J, Hipfner DR, Stark A, Russell RB and Cohen SM: bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 113:25–36. 2003. View Article : Google Scholar : PubMed/NCBI
9	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
10	Su H, Yang JR, Xu T, et al: MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 69:1135–1142. 2009. View Article : Google Scholar : PubMed/NCBI
11	Lu J, Getz G, Miska EA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
12	Yanaihara N, Caplen N, Bowman E, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI
13	Iorio MV, Visone R, Di Leva G, et al: MicroRNA signatures in human ovarian cancer. Cancer Res. 67:8699–8707. 2007. View Article : Google Scholar : PubMed/NCBI
14	Murakami Y, Yasuda T, Saigo K, et al: Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 25:2537–2545. 2006. View Article : Google Scholar : PubMed/NCBI
15	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
16	Krek A, Grün D, Poy MN, et al: Combinatorial microRNA target predictions. Nat Genet. 37:495–500. 2005. View Article : Google Scholar
17	Volinia S, Calin GA, Liu CG, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
18	Massagué J: G1 cell-cycle control and cancer. Nature. 432:298–306. 2004.
19	Deshpande A, Sicinski P and Hinds PW: Cyclins and cdks in development and cancer: a perspective. Oncogene. 24:2909–2915. 2005. View Article : Google Scholar : PubMed/NCBI
20	Wang W, Zhao LJ, Tan YX, Ren H and Qi ZT: MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma. Carcinogenesis. 33:1113–1120. 2012. View Article : Google Scholar : PubMed/NCBI
21	Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP and Zhuang SM: MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology. 50:113–121. 2009. View Article : Google Scholar : PubMed/NCBI
22	Baffa R, Fassan M, Volinia S, et al: MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol. 219:214–221. 2009. View Article : Google Scholar : PubMed/NCBI
23	Gregory PA, Bert AG, Paterson EL, et al: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
24	Ahn SM, Cha JY, Kim J, et al: Smad3 regulates E-cadherin via miRNA-200 pathway. Oncogene. 31:3051–3059. 2012. View Article : Google Scholar : PubMed/NCBI
25	Saydam O, Shen Y, Würdinger T, et al: Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol. 29:5923–5940. 2009. View Article : Google Scholar : PubMed/NCBI
26	Xia H, Ng SS, Jiang S, et al: miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem Biophys Res Commun. 391:535–541. 2010. View Article : Google Scholar : PubMed/NCBI
27	Hung CS, Liu HH, Liu JJ, et al: MicroRNA-200a and -200b mediated hepatocellular carcinoma cell migration through the epithelial to mesenchymal transition markers. Ann Surg Oncol. Aug 7–2012.(Epub ahead of print).
28	Lee JW, Park YA, Choi JJ, et al: The expression of the miRNA-200 family in endometrial endometrioid carcinoma. Gynecol Oncol. 120:56–62. 2011. View Article : Google Scholar : PubMed/NCBI
29	Grillo M, Bott MJ, Khandke N, et al: Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression. Breast Cancer Res Treat. 95:185–194. 2006. View Article : Google Scholar
30	Bagchi A and Mills AA: The quest for the 1p36 tumor suppressor. Cancer Res. 68:2551–2556. 2008. View Article : Google Scholar : PubMed/NCBI
31	Sato Y, Kobayashi H, Suto Y, et al: Chromosomal instability in chromosome band 12p13: multiple breaks leading to complex rearrangements including cytogenetically undetectable sub-clones. Leukemia. 15:1193–1202. 2001. View Article : Google Scholar