miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1

Yu,Junjie; Lu,Youyi; Cui,Di; Li,Enhui; Zhu,Yipin; Zhao,Yuyang; Zhao,Fujun; Xia,Shujie

doi:10.3892/or.2013.2897

miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1

Authors:
- Junjie Yu
- Youyi Lu
- Di Cui
- Enhui Li
- Yipin Zhu
- Yuyang Zhao
- Fujun Zhao
- Shujie Xia
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Affiliations: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
Published online on: December 5, 2013 https://doi.org/10.3892/or.2013.2897
Pages: 910-918

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Abstract

microRNAs (miRNAs) are a class of small non-coding RNAs that can post-transcriptionally regulate gene expression and play critical roles in many important biological processes. The role of miRNAs in prostate cancer (PCa) development and pathogenesis remains largely unknown. In the present study, we showed that miR-200b was downregulated in clinical prostatic tumors when compared to normal prostate tissue and in advanced PCa cell lines when compared to normal epithelial prostatic cells. Enforced miR-200b expression suppressed PCa cell proliferation and migration and enhanced chemosensitivity to docetaxel by targeting B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1). Bmi-1 was detected at higher levels in PCa, and knockdown of Bmi-1 showed similar effects as miR-200b overexpression in PCa cells. Moreover, we confirmed that these effects were correlated with increased levels of E-cadherin and P16 and a reduction in vimentin expression and expression of stem cell markers (CD44 and OCT4). These findings suggest that miR-200b plays vital roles as a tumor-suppressor by targeting Bmi-1 and may be a promising therapeutic target for PCa treatment.

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1	Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI
2	Damber JE and Aus G: Prostate cancer. Lancet. 371:1710–1721. 2008. View Article : Google Scholar : PubMed/NCBI
3	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
4	Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G and Tuschl T: Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 15:185–197. 2004. View Article : Google Scholar : PubMed/NCBI
5	Feng B, Wang R and Chen LB: Review of miR-200b and cancer chemosensitivity. Biomed Pharmacother. 66:397–402. 2012. View Article : Google Scholar : PubMed/NCBI
6	Zhu W, Xu H, Zhu D, et al: miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP. Cancer Chemother Pharmacol. 69:723–731. 2012. View Article : Google Scholar : PubMed/NCBI
7	Wellner U, Schubert J, Burk UC, et al: The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 11:1487–1495. 2009. View Article : Google Scholar : PubMed/NCBI
8	Guo BH, Feng Y, Zhang R, et al: Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer. Mol Cancer. 10:102011. View Article : Google Scholar : PubMed/NCBI
9	Bhattacharya R, Nicoloso M, Arvizo R, et al: MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer. Cancer Res. 69:9090–9095. 2009. View Article : Google Scholar : PubMed/NCBI
10	Song W, Tao K, Li H, et al: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci. 101:1754–1760. 2010. View Article : Google Scholar : PubMed/NCBI
11	He X, Dong Y, Wu CW, et al: MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med. 18:1491–1498. 2013.PubMed/NCBI
12	Song LB, Li J, Liao WT, et al: The polycomb group protein Bmi-1 represses the tumor-suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 119:3626–3636. 2009. View Article : Google Scholar
13	Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ: Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 425:962–967. 2003. View Article : Google Scholar : PubMed/NCBI
14	Lukacs RU, Memarzadeh S, Wu H and Witte ON: Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell. 7:682–693. 2010. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Onder TT, Kara N, Cherry A, et al: Chromatin-modifying enzymes as modulators of reprogramming. Nature. 483:598–602. 2012. View Article : Google Scholar : PubMed/NCBI
17	Korpal M, Lee ES, Hu G and Kang Y: The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 283:14910–14914. 2008. View Article : Google Scholar : PubMed/NCBI
18	Fan C, He L, Kapoor A, et al: Bmi1 promotes prostate tumorigenesis via inhibiting p16^INK4A and p14^ARF expression. Biochim Biophys Acta. 1782:642–648. 2008. View Article : Google Scholar : PubMed/NCBI
19	Dong P, Kaneuchi M, Watari H, et al: MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer. 10:992011. View Article : Google Scholar : PubMed/NCBI
20	Schaefer A, Jung M, Mollenkopf HJ, et al: Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 126:1166–1176. 2010.PubMed/NCBI
21	Kong D, Banerjee S, Ahmad A, et al: Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One. 5:e124452010. View Article : Google Scholar : PubMed/NCBI
22	Park SM, Gaur AB, Lengyel E and Peter ME: The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22:894–907. 2008. View Article : Google Scholar : PubMed/NCBI
23	Liu YN, Yin JJ, Abou-Kheir W, et al: MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene. 32:296–306. 2013. View Article : Google Scholar : PubMed/NCBI
24	Tang H, Kong Y, Guo J, et al: Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by up-regulation of miR-200b and miR-22. Cancer Lett. 340:72–81. 2013. View Article : Google Scholar : PubMed/NCBI
25	Pacurari M, Addison JB, Bondalapati N, et al: The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol. 43:548–560. 2013.PubMed/NCBI
26	Yoshino H, Enokida H, Itesako T, et al: Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. J Hum Genet. 58:508–516. 2013. View Article : Google Scholar : PubMed/NCBI
27	Köhler CU, Bryk O, Meier S, et al: Analyses in human urothelial cells identify methylation of miR-152, miR-200b and miR-10a genes as candidate bladder cancer biomarkers. Biochem Biophys Res Commun. 438:48–53. 2013.
28	Cao Q, Mani RS, Ateeq B, et al: Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 20:187–199. 2011. View Article : Google Scholar : PubMed/NCBI
29	Sun L, Yao Y, Liu B, et al: MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene. 31:432–445. 2012. View Article : Google Scholar : PubMed/NCBI
30	Kang MK, Kim RH, Kim SJ, et al: Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br J Cancer. 96:126–133. 2007. View Article : Google Scholar : PubMed/NCBI
31	Siddique HR and Saleem M: Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 30:372–378. 2012. View Article : Google Scholar : PubMed/NCBI
32	Siddique HR, Parray A, Tarapore RS, et al: BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling. PLoS One. 8:e606642013. View Article : Google Scholar : PubMed/NCBI
33	Wolters T, Vissers KJ, Bangma CH, Schröder FH and van Leenders GJ: The value of EZH2, p27^kip1, BMI-1 and MIB-1 on biopsy specimens with low-risk prostate cancer in selecting men with significant prostate cancer at prostatectomy. BJU Int. 106:280–286. 2010.PubMed/NCBI
34	van Leenders GJ, Dukers D, Hessels D, et al: Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol. 52:455–463. 2007.PubMed/NCBI
35	Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M: The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 397:164–168. 1999. View Article : Google Scholar : PubMed/NCBI
36	Crea F, Duhagon Serrat MA, Hurt EM, Thomas SB, Danesi R and Farrar WL: BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer. 128:1946–1954. 2011. View Article : Google Scholar : PubMed/NCBI
37	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
38	Sánchez-Tilló E, Lázaro A, Torrent R, et al: ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 29:3490–3500. 2010.PubMed/NCBI
39	Yang MH, Hsu DS, Wang HW, et al: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 12:982–992. 2010. View Article : Google Scholar : PubMed/NCBI