Overexpressed MiR-200a Promotes Bladder Cancer Invasion Through Direct Regulating Dicer/miR-16/JNK2/MMP-2 Axis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2019 Nov 28

PMID 31772330

Citations 29

Authors

Rui Yang

Jiheng Xu

Xiaohui Hua

Zhongxian Tian

Qipeng Xie

Jingxia Li

Guosong Jiang

Mitchell Cohen

Hong Sun

Chuanshu Huang

Affiliations

Soon will be listed here.

Abstract

Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.

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References

Burger M, Catto J, Dalbagni G, Grossman H, Herr H, Karakiewicz P . Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2012; 63(2):234-41. DOI: 10.1016/j.eururo.2012.07.033. View

Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F . Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol. 2016; 71(1):96-108. DOI: 10.1016/j.eururo.2016.06.010. View

Kaufman D, Shipley W, Feldman A . Bladder cancer. Lancet. 2009; 374(9685):239-49. DOI: 10.1016/S0140-6736(09)60491-8. View

van Rhijn B, Burger M, Lotan Y, Solsona E, Stief C, Sylvester R . Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009; 56(3):430-42. DOI: 10.1016/j.eururo.2009.06.028. View

Pectasides D, Pectasides M, Nikolaou M . Adjuvant and neoadjuvant chemotherapy in muscle invasive bladder cancer: literature review. Eur Urol. 2005; 48(1):60-7. DOI: 10.1016/j.eururo.2005.03.025. View

Chen Y, Zhang L . Members of the microRNA-200 family are promising therapeutic targets in cancer. Exp Ther Med. 2017; 14(1):10-17. PMC: 5488420. DOI: 10.3892/etm.2017.4488. View

Gregory P, Bert A, Paterson E, Barry S, Tsykin A, Farshid G . The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008; 10(5):593-601. DOI: 10.1038/ncb1722. View

Park S, Gaur A, Lengyel E, Peter M . The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008; 22(7):894-907. PMC: 2279201. DOI: 10.1101/gad.1640608. View

Korpal M, Lee E, Hu G, 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. 2008; 283(22):14910-4. PMC: 3258899. DOI: 10.1074/jbc.C800074200. View

10.

Katoh Y, Katoh M . Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008; 22(3):271-5. View

11.

Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol R . Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol. 2006; 169(5):1812-20. PMC: 1780192. DOI: 10.2353/ajpath.2006.060480. View

12.

Pampalakis G, Diamandis E, Katsaros D, Sotiropoulou G . Down-regulation of dicer expression in ovarian cancer tissues. Clin Biochem. 2009; 43(3):324-7. DOI: 10.1016/j.clinbiochem.2009.09.014. View

13.

Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K . Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 2005; 96(2):111-5. PMC: 11158408. DOI: 10.1111/j.1349-7006.2005.00015.x. View

14.

Jakymiw A, Patel R, Deming N, Bhattacharyya I, Shah P, Lamont R . Overexpression of dicer as a result of reduced let-7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells. Genes Chromosomes Cancer. 2010; 49(6):549-59. PMC: 2859695. DOI: 10.1002/gcc.20765. View

15.

Nelson P, Kiriakidou M, Sharma A, Maniataki E, Mourelatos Z . The microRNA world: small is mighty. Trends Biochem Sci. 2003; 28(10):534-40. DOI: 10.1016/j.tibs.2003.08.005. View

16.

Carmell M, Hannon G . RNase III enzymes and the initiation of gene silencing. Nat Struct Mol Biol. 2004; 11(3):214-8. DOI: 10.1038/nsmb729. View

17.

Grelier G, Voirin N, Ay A, Cox D, Chabaud S, Treilleux I . Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer. 2009; 101(4):673-83. PMC: 2736830. DOI: 10.1038/sj.bjc.6605193. View

18.

Zhang Z, Zhang G, Kong C, Bi J, Gong D, Yu X . EIF2C, Dicer, and Drosha are up-regulated along tumor progression and associated with poor prognosis in bladder carcinoma. Tumour Biol. 2015; 36(7):5071-9. DOI: 10.1007/s13277-015-3158-z. View

19.

Wu D, Tao J, Xu B, Li P, Lu Q, Zhang W . Downregulation of Dicer, a component of the microRNA machinery, in bladder cancer. Mol Med Rep. 2011; 5(3):695-9. DOI: 10.3892/mmr.2011.711. View

20.

Tao J, Wu D, Li P, Xu B, Lu Q, Zhang W . microRNA-18a, a member of the oncogenic miR-17-92 cluster, targets Dicer and suppresses cell proliferation in bladder cancer T24 cells. Mol Med Rep. 2011; 5(1):167-72. DOI: 10.3892/mmr.2011.591. View