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.
Highlights
MicroRNAs are recognized as a group of small noncoding RNAs that play diverse roles in regulation of biological processes and have a unique expression profile that varies in a tissue and disease specific manner [1, 2]
MiR-17-92a cluster miRNAs are transcribed from the polycistronic miR-17-92a gene located in the third intron of a primary transcript C13orf25 [9] that is processed into six mature miRNAs viz. miR-17, miR18a, miR-19a, miR-19b, miR-20a and miR-92a [10]. miR-17-92a cluster has been differentially expressed in various cancers [11,12,13] and based on the function of the target genes, has been designated as oncogenic miRNAs [14, 15]
Published reports show anti-proliferative www.impactjournals.com/oncotarget and senescence promoting effects of the members of the miR-17-92a clusters through direct targeting of Dicer by miR-18a in bladder cancer cells [19]; through downregulation of the Amplified In Breast cancer 1 (AIB) mRNAs by miR-17-5p [20]; and through destabilization of proto-oncogene Leukemia Related Factor (LRF) mRNA by miR-20a [21]
Summary
MicroRNAs (miRNA) are recognized as a group of small noncoding RNAs that play diverse roles in regulation of biological processes and have a unique expression profile that varies in a tissue and disease specific manner [1, 2]. Published reports show anti-proliferative www.impactjournals.com/oncotarget and senescence promoting effects of the members of the miR-17-92a clusters through direct targeting of Dicer by miR-18a in bladder cancer cells [19]; through downregulation of the Amplified In Breast cancer 1 (AIB) mRNAs by miR-17-5p [20]; and through destabilization of proto-oncogene Leukemia Related Factor (LRF) mRNA by miR-20a [21]. These effects further emphasize the contextual aspects of the functional complexities of miR17-92a cluster. In depth understanding of the function of the miR-1792a cluster miRNAs in prostate cancer growth and drug resistance is lacking
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