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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6

Authors: Bairong Xia, Shanshan Yang, Tianbo Liu, Ge Lou

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

Epithelial ovarian cancer (EOC) is a significant cause of morbidity and mortality. MicroRNAs play important roles in cancer development and progression. The microRNA miR-211 is localized on intron 6 of the Trpm1 gene at 15q13-q14, a locus that is frequently lost in neoplasms. Its function and loss-of-function have been described in normal and cancer cells and tissues. miR-211 is known to be dysregulated in ovarian cancer: however, its function and the downstream effect of its loss-of-function in ovarian cancer have not been described before.

Methods

We analyzed miR-211 expression in clinical samples of primary EOC tissues compared to normal epithelial ovarian tissues and in the EOC cell lines: OVCAR3, Caov3, OVCA429, SKOV3 and A2780 compared to human ovarian surface epithelial cells. We then investigated the effect of miR-211 on EOC cell proliferation and apoptosis by counting cell numbers, MTT, colony formation, cell cycle, and PI/Annexin V staining assays. A luciferase reporter system was developed to assess miR-211 regulation of the predicted targets. Expression level of discovered targets and correlation with miR-211 expression were analyzed in EOC tissues. Finally, OVCAR3 stably expressing miR-211 or control cells were injected subcutaneously into mice to determine in vivo effect of miR-211 on tumorigenesis.

Results

We found that the expression of miR-211 is downregulated in EOC tissues and cell lines compared to normal epithelial ovarian tissue and human ovarian surface epithelial cells, respectively. miR-211 was found to arrest cells in the G0/G1-phase, inhibit proliferation and induce apoptosis. Cyclin D1 and CDK6 were found to be direct targets of miR-211, and when overexpressed in miR-211-expressing EOC cells, could restore proliferative ability. Finally, in vitro investigation confirmed that miR-211 is a tumor suppressor that controls Cyclin D1 and CDK6 expression.

Conclusions

Our results demonstrate that miR-211 is a tumor suppressor that controls expression of Cyclin D1 and CDK6, and that its downregulation results in overexpression of Cyclin D1 and CDK6 which increases proliferation ability of EOC cells to proliferate compared to normal cells.
Appendix
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Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMed
2.
3.
Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S161–92.CrossRefPubMed
4.
5.
6.
7.
Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653–62.CrossRefPubMed
8.
Mazar J, DeYoung K, Khaitan D, Meister E, Almodovar A, Goydos J, et al. The regulation of miRNA-211 expression and its role in melanoma cell invasiveness. PLoS ONE. 2010;5:e13779.CrossRefPubMedCentralPubMed
9.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.CrossRefPubMed
10.
Yang N, Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, et al. MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res. 2008;68:10307–14.CrossRefPubMedCentralPubMed
11.
Mitamura T, Watari H, Wang L, Kanno H, Hassan MK, Miyazaki M, et al. Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. Oncogenesis. 2013;2:e40.CrossRefPubMedCentralPubMed
12.
Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ. 2010;17:215–20.CrossRefPubMed
13.
Feenstra M, Veltkamp M, van Kuik J, Wiertsema S, Slootweg P, van den Tweel J, et al. HLA class I expression and chromosomal deletions at 6p and 15q in head and neck squamous cell carcinomas. Tissue Antigens. 1999;54:235–45.CrossRefPubMed
14.
Natrajan R, Louhelainen J, Williams S, Laye J, Knowles MA. High-resolution deletion mapping of 15q13.2-q21.1 in transitional cell carcinoma of the bladder. Cancer Res. 2003;63:7657–62.PubMed
15.
16.
Poetsch M, Kleist B. Loss of heterozygosity at 15q21.3 correlates with occurrence of metastases in head and neck cancer. Mod Pathol. 2006;19:1462–9.PubMed
17.
Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, et al. miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol Cell. 2012;48:353–64.CrossRefPubMedCentralPubMed
18.
Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005;24:3470–81.CrossRefPubMedCentralPubMed
19.
Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene. 2010;29:3881–95.CrossRefPubMedCentralPubMed
20.
Gupta S, McGrath B, Cavener DR. PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice. PLoS ONE. 2009;4:e8008.CrossRefPubMedCentralPubMed
21.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000;5:897–904.CrossRefPubMed
22.
Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol. 2002;22:3864–74.CrossRefPubMedCentralPubMed
23.
Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006;12:406–14.CrossRefPubMed
24.
Bell RE, Khaled M, Netanely D, Schubert S, Golan T, Buxbaum A, et al. Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting NUAK1. J Invest Dermatol. 2014;134:441–51.CrossRefPubMed
25.
Asuthkar S, Velpula KK, Chetty C, Gorantla B, Rao JS. Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity. Oncotarget. 2012;3:1439–54.PubMedCentralPubMed
26.
Chang KW, Liu CJ, Chu TH, Cheng HW, Hung PS, Hu WY, et al. Association between High miR-211 microRNA Expression and the Poor Prognosis of Oral Carcinoma. J Dent Res. 2008;87:1063–8.CrossRefPubMed
27.
Vilming Elgaaen B, Olstad OK, Haug KB, Brusletto B, Sandvik L, Staff AC, et al. Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker. BMC Cancer. 2014;14:80.CrossRefPubMedCentralPubMed
28.
Yoshioka S, King ML, Ran S, Okuda H, MacLean 2nd JA, McAsey ME, et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Mol Cancer Res. 2012;10:469–82.CrossRefPubMedCentralPubMed
29.
Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol. 2004;287:C281–91.CrossRefPubMed
30.
Wu W, Slomovitz BM, Soliman PT, Schmeler KM, Celestino J, Milam MR, et al. Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma. Int J Gynecol Cancer. 2006;16:1668–72.CrossRefPubMed
31.
Sakuma M, Akahira J, Ito K, Niikura H, Moriya T, Okamura K, et al. Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer. Cancer Sci. 2007;98:380–6.CrossRefPubMed
32.
Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genomics. 2009;2:71.CrossRefPubMedCentralPubMed
33.
Dong Q, Meng P, Wang T, Qin W, Wang F, Yuan J, et al. MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS ONE. 2010;5:e10147.CrossRefPubMedCentralPubMed
34.
Iorio MV, Casalini P, Piovan C, Braccioli L, Tagliabue E. Breast cancer and microRNAs: therapeutic impact. Breast. 2011;20 Suppl 3:S63–70.CrossRefPubMed
35.
Kim SJ, Shin JY, Lee KD, Bae YK, Sung KW, Nam SJ, et al. MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7. Breast Cancer Res. 2012;14:R14.CrossRefPubMedCentralPubMed
36.
37.
Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11:558–72.CrossRefPubMed
38.
Zhang Z, Huang L, Yu Z, Chen X, Yang D, Zhan P, et al. Let-7a functions as a tumor suppressor in Ewing’s sarcoma cell lines partly by targeting cyclin-dependent kinase 6. DNA Cell Biol. 2014;33:136–47.CrossRefPubMedCentralPubMed
39.
Grossel MJ, Hinds PW. Beyond the cell cycle: a new role for Cdk6 in differentiation. J Cell Biochem. 2006;97:485–93.CrossRefPubMed
40.
Wiedemeyer WR, Dunn IF, Quayle SN, Zhang J, Chheda MG, Dunn GP, et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A. 2010;107:11501–6.CrossRefPubMedCentralPubMed
41.
Tsai JW, Li CF, Kao YC, Wang JW, Fang FM, Wang YH, et al. Recurrent amplification at 7q21.2 Targets CDK6 gene in primary myxofibrosarcomas and identifies CDK6 overexpression as an independent adverse prognosticator. Ann Surg Oncol. 2012;19:2716–25.CrossRefPubMed
42.
Nagel S, Leich E, Quentmeier H, Meyer C, Kaufmann M, Drexler HG, et al. Amplification at 7q22 targets cyclin-dependent kinase 6 in T-cell lymphoma. Leukemia. 2008;22:387–92.CrossRefPubMed
43.
Ando K, Ajchenbaum-Cymbalista F, Griffin JD. Regulation of G1/S transition by cyclins D2 and D3 in hematopoietic cells. Proc Natl Acad Sci U S A. 1993;90:9571–5.CrossRefPubMedCentralPubMed
44.
45.
Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, et al. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993;7:1559–71.CrossRefPubMed
46.
Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993;7:812–21.CrossRefPubMed
47.
Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J, Livingston DM. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993;73:487–97.CrossRefPubMed
48.
Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992;70:993–1006.CrossRefPubMed
49.
Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994;14:2077–86.PubMedCentralPubMed
50.
Grossel MJ, Hinds PW. From cell cycle to differentiation: an expanding role for cdk6. Cell Cycle. 2006;5:266–70.CrossRefPubMed
51.
Handschick K, Beuerlein K, Jurida L, Bartkuhn M, Muller H, Soelch J, et al. Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-kappaB-dependent gene expression. Mol Cell. 2014;53:193–208.CrossRefPubMed
52.
Li B, He H, Tao BB, Zhao ZY, Hu GH, Luo C, et al. Knockdown of CDK6 enhances glioma sensitivity to chemotherapy. Oncol Rep. 2012;28:909–14.PubMed
53.
Wu ZS, Wang CQ, Xiang R, Liu X, Ye S, Yang XQ, et al. Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion. BMC Cancer. 2012;12:51.CrossRefPubMedCentralPubMed
Metadata
Title
miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6
Authors
Bairong Xia
Shanshan Yang
Tianbo Liu
Ge Lou
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0322-4

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