Oncotarget

Research Papers:

The other face of miR-17-92a cluster, exhibiting tumor suppressor effects in prostate cancer

Richard Ottman, Jenna Levy, Williams E. Grizzle and Ratna Chakrabarti _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:73739-73753. https://doi.org/10.18632/oncotarget.12061

Metrics: PDF 827 views  |   HTML 1566 views  |   ?  


Abstract

Richard Ottman1, Jenna Levy1, William E. Grizzle2, Ratna Chakrabarti1

1Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA

2Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence to:

Ratna Chakrabarti, email: Ratna.Chakrabarti@ucf.edu

Keywords: miR-17-92a cluster, prostate cancer, tumor suppressor

Received: February 28, 2016     Accepted: September 02, 2016     Published: September 16, 2016

ABSTRACT

miR-17-92a cluster miRNAs are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a that are overexpressed in lung and colon cancers. Here we show that the expression of miR-17-92a miRNAs are reduced in cancerous prostate tissues compared to uninvolved areas and also in aggressive prostate cancer cells. Restoration of expression of all members of miR-17-92a cluster showed, decreased expression of cell cycle regulatory proteins cyclin D1 and SSH1; and LIMK1 and FGD4 of RhoGTPase signaling pathway. Expression of miR-17-92a miRNAs caused decreased cell proliferation, reduced activation of AKT and MAP kinases, delayed tumorigenicity and reduced tumor growth in animals. Expression of miR-17-92a miRNAs inhibited EMT via reduced cell migration and expression of mesenchymal markers while elevating expression and surface localization of the epithelial marker E-Cadherin. Expression of miR-17-92a miRNAs improved sensitivity of androgen dependent LNCaP 104-S prostate cancer cells to anti-androgen drug Casodex, AKT inhibitor MK-2206 2HCl, and docetaxel. The androgen refractory PC-3 cells also showed increased sensitivity to docetaxel, MK-2206 2HCl and Aurora kinase inhibitor VX680 upon ectopic expression of miR-17-92a cluster miRNAs. Our data demonstrate a tumor suppressor effect of miR-17-92a cluster miRNAs in prostate cancer cells and restoration of expression of these miRNAs has a therapeutic benefit for both androgen-dependent and -independent prostate cancer cells.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 12061