Abstract
MicroRNA-30c (miR-30c) acts as a tumor suppressor or a tumor promoter in various human malignancies. However, the involvement of miR-30c in prostate cancer (PCa) is still unclear. The aim of this study was to investigate the molecular function and the clinical significance of miR-30c in PCa. Expression levels of miR-30c in PCa tissues and cells were detected by quantitative real-time-PCR (qRT-PCR). Additionally, the associations of miR-30c expression with clinicopathological features and prognosis in PCa patients were analyzed. The potential role of miR-30c in tumorigenesis of PCa cells was further evaluated by in vitro cell assays. MiR-30c was significantly down-regulated in PCa tissues and cells compared with the corresponding controls (P < 0.05). In addition, the downregulation of miR-30c in PCa tissues was significantly associated with higher Gleason score (P = 0.009), advanced pathological stage (P = 0.016) and biochemical recurrence (P = 0.034). Moreover, Kaplan–Meier survival analysis showed that the reduced expression of miR-30c was correlated with shorter biochemical recurrence-free survival (P = 0.023). The multivariate analysis also identified miR-30c as an independent prognostic predictor for biochemical recurrence-free survival in patients with PCa. Furthermore, the enforced expression of miR-30c suppressed proliferation, migration and invasion of PCa cells in vitro. Our data indicated the involvement of miR-30c in PCa progression and suggested its potential role as an independent predictor of biochemical recurrence in PCa. On cellular level, miR-30c may function as a tumor suppressor for PCa cells by inhibiting tumor cell proliferation, migration and invasion.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781
Utomo NB, Mochtar CA, Umbas R (2012) Primary hormonal treatment in localized and locally advanced prostate cancer: effectiveness and survival predictive factors. Acta Med Indones 44:10–15
Dasgupta S, Srinidhi S, Vishwanatha JK (2012) Oncogenic activation in prostate cancer progression and metastasis: molecular insights and future challenges. J Carcinog 11:4
Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, Ekman P, DeMarzo AM, Tibshirani R, Botstein D, Brown PO, Brooks JD, Pollack JR (2004) Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA 101:811–816
Kurdistani SK (2007) Histone modifications as markers of cancer prognosis: a cellular view. Br J Cancer 97:1–5
Wu Q, Song R, Ortogero N, Zheng H, Evanoff R, Small CL, Griswold MD, Namekawa SH, Royo H, Turner JM, Yan W (2012) The RNase III enzyme DROSHA is essential for microRNA production and spermatogenesis. J Biol Chem 287:25173–25190
Plaisier CL, Pan M, Baliga NS (2012) A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers. Genome Res 22:2302–2314
Kent OA, Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25:6188–6196
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down regulation of micro-RNA genes miR15 e miR16 and 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529
Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M (2008) MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 47:1223–1232
Ozen M, Creighton CJ, Ozdemir M, Ittmann M (2008) Wide-spread deregulation of microRNA expression in human prostate cancer. Oncogene 27:1788–1793
He HC, Zhu JG, Chen XB, Chen SM, Han ZD, Dai QS, Ling XH, Fu X, Lin ZY, Deng YH, Qin GQ, Cai C, Chen JH, Zhong WD (2012) MicroRNA-23b downregulates peroxiredoxin III in human prostate cancer. FEBS Lett 586:2451–2458
Xiong SW, Lin TX, Xu KW, Dong W, Ling XH, Jiang FN, Chen G, Zhong WD, Huang J (2013) MicroRNA-335 Acts as a candidate tumor suppressor in prostate cancer. Pathol Oncol Res 19:529–537
Lee H, Park CS, Deftereos G, Morihara J, Stern JE, Hawes SE, Swisher E, Kiviat NB, Feng Q (2012) MicroRNA expression in ovarian carcinoma and its correlation with clinicopathological features. World J Surg Oncol 10:174
Busacca S, Germano S, De Cecco L, Rinaldi M, Comoglio F, Favero F, Murer B, Mutti L, Pierotti M, Gaudino G (2010) MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications. Am J Respir Cell Mol Biol 42:312–319
Benner MF, Ballabio E, van Kester MS, Saunders NJ, Vermeer MH, Willemze R, Lawrie CH, Tensen CP (2012) Primary cutaneous anaplastic large cell lymphoma shows a distinct miRNA expression profile and reveals differences from tumor-stage mycosis fungoides. Exp Dermatol 21:632–634
Tanic M, Yanowsky K, Rodriguez-Antona C, Andrés R, Márquez-Rodas I, Osorio A, Benitez J, Martinez-Delgado B (2012) Deregulated miRNAs in hereditary breast cancer revealed a role for miR-30c in regulating KRAS oncogene. PLoS ONE 7:e38847
Heinzelmann J, Henning B, Sanjmyatav J, Posorski N, Steiner T, Wunderlich H, Gajda MR, Junker K (2011) Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol 29:367–373
Wang G, Zhang H, He H, Tong W, Wang B, Liao G, Chen Z, Du C (2010) Up-regulation of microRNA in bladder tumor tissue is not common. Int Urol Nephrol 42:95–102
Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T (2007) MicroRNA expression profiling in prostate cancer. Cancer Res 67:6130–6135
Chen ZH, Zhang GL, Li HR, Luo JD, Li ZX, Chen GM, Yang J (2012) A panel of five circulating microRNAs as potential biomarkers for prostate cancer. Prostate 72:1443–1452
Hanley JA, McNeil BJ (1982) The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143:29–36
Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D’Urso L, Pagliuca A, Biffoni M, Labbaye C, Bartucci M, Muto G, Peschle C, De Maria R (2008) The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14:1271–1277
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838
Fendler A, Jung M, Stephan C, Honey RJ, Stewart RJ, Pace KT, Erbersdobler A, Samaan S, Jung K, Yousef GM (2011) miRNAs can predict prostate cancer biochemical relapse and are involved in tumor progression. Int J Oncol 39:1183–1192
Schaefer A, Stephan C, Busch J, Yousef GM, Jung K (2010) Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors. Nat Rev Urol 7:286–297
Yu F, Deng H, Yao H, Liu Q, Su F, Song E (2010) Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene 29:4194–4204
Zhou H, Xu X, Xun Q, Yu D, Ling J, Guo F, Yan Y, Shi J, Hu Y (2012) microRNA-30c negatively regulates endometrial cancer cells by targeting metastasis-associated gene-1. Oncol Rep 27:807–812
Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, Sun J, Lovat F, Alder H, Condorelli G, Engelman JA, Ono M, Rho JK, Cascione L, Volinia S, Nephew KP, Croce CM (2011) EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 18:74–82
Wu F, Zhu S, Ding Y, Beck WT, Mo YY (2009) MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res 15:1550–1557
Gong J, Liu R, Zhuang R, Zhang Y, Fang L, Xu Z, Jin L, Wang T, Song C, Yang K, Wei Y, Yang A, Jin B, Chen L (2012) miR-30c-1* promotes natural killer cell cytotoxicity against human hepatoma cells by targeting the transcription factor HMBOX1. Cancer Sci 103:645–652
Wang XS, Shankar S, Dhanasekaran SM, Ateeq B, Sasaki AT, Jing X, Robinson D, Cao Q, Prensner JR, Yocum AK, Wang R, Fries DF, Han B, Asangani IA, Cao X, Li Y, Omenn GS, Pflueger D, Gopalan A, Reuter VE, Kahoud ER, Cantley LC, Rubin MA, Palanisamy N, Varambally S, Chinnaiyan AM (2011) Characterization of KRAS rearrangements in metastatic prostate cancer. Cancer Discov 1:35–43
Kim JH, Lee JM, Nam HJ, Choi HJ, Yang JW, Lee JS, Kim MH, Kim SI, Chung CH, Kim KI, Baek SH (2007) SUMOylation of pontin chromatin-remodeling complex reveals a signal integration code in prostate cancer cells. Proc Natl Acad Sci USA 104:20793–20798
Wang H, Fan L, Wei J, Weng Y, Zhou L, Shi Y, Zhou W, Ma D, Wang C (2012) Akt mediates metastasis-associated gene 1 (MTA1) regulating the expression of E-cadherin and promoting the invasiveness of prostate cancer cells. PLoS ONE 7:e46888
Kao CJ, Martiniez A, Shi XB, Yang J, Evans CP, Dobi A, Devere White RW, Kung HJ (2013) miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT. Oncogene. doi:10.1038/onc.2013.200
Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, Steuber T, Beissbarth T, Kuner R, Sültmann H (2011) Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer 128:608–616
Rodríguez-González FG, Sieuwerts AM, Smid M, Look MP, Meijer-van Gelder ME, de Weerd V, Sleijfer S, Martens JW, Foekens JA (2011) MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat 127:43–51
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC (1999) Natural history of progression after PSA elevation: following radical prostatectomy. JAMA 281:1591–1597
Li T, Li RS, Li YH, Zhong S, Chen YY, Zhang CM, Hu MM, Shen ZJ (2012) miR-21 as an independent biochemical recurrence predictor and potential therapeutic target for prostate cancer. J Urol 187:1466–1472
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This work was supported by grants from Key Personnel Plan of Zhejiang Province Medical and Health Platform (Class A) (2011RCA019), National Natural Science Foundation of China (81170699, 81272813, 81200550), Science and Technology Project of Guangdong Province (2012B031800008), Medical Research Fund of Guangdong Province (A2012489), Guangzhou Municipal Science and Technology Key Project (11C23150711), Key Projects of Bureau of Health in Guangzhou Municipality (201102A212015).
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Xiao-hui Ling, Zhao-dong Han and Dan Xia contributed equally to this work.
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Ling, Xh., Han, Zd., Xia, D. et al. MicroRNA-30c serves as an independent biochemical recurrence predictor and potential tumor suppressor for prostate cancer. Mol Biol Rep 41, 2779–2788 (2014). https://doi.org/10.1007/s11033-014-3132-7
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DOI: https://doi.org/10.1007/s11033-014-3132-7