Oncomir miR-125b Suppresses p14ARF to Modulate p53-Dependent and p53-Independent Apoptosis in Prostate Cancer

PLoS One

Hsing-Jien Kung¹  Ralph W. deVere White²  Xu-Bao Shi²  Sumaira Amir²  Lingru Xue²  Ai-Hong Ma² 

[1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, California, United States of America;Department of Urology, University of California Davis, Sacramento, California, United States of America

关键词: Apoptosis;    MicroRNAs;    Cell proliferation;    Cancer treatment;    Small interfering RNAs;    Luciferase;    Prostate cancer;    Tumor suppressor genes;   

DOI  :  10.1371/journal.pone.0061064

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

MicroRNAs are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level and regulate complex patterns of gene expression. Our previous studies demonstrated that in human prostate cancer the miRNA miR-125b is highly expressed, leading to a negative regulation of some tumor suppressor genes. In this study, we further extend our studies by showing that miR-125b represses the protein product of the ink4a/ARF locus, p14ARF, in two prostate cancer cell lines, LNCaP (wild type-p53) and 22Rv1 (both wild type and mutant p53), as well as in the PC-346C prostate cancer xenograft model that lentivirally overexpressed miR-125b. Our results highlight that miR-125b modulates the p53 network by hindering the down-regulation of Mdm2, thereby affecting p53 and its target genes p21 and Puma to a degree sufficient to inhibit apoptosis. Conversely, treatment of prostate cancer cells with an inhibitor of miR-125b (anti-miR-125b) resulted in increased expression of p14ARF, decreased level of Mdm2, and induction of apoptosis. In addition, overexpression of miR-125b in p53-deficient PC3 cells induced down-regulation of p14ARF, which leads to increased cell proliferation through a p53-independent manner. Thus, we conclude that miR-125b acts as an oncogene which regulates p14ARF/Mdm2 signaling, stimulating proliferation of prostate cancer cells through a p53-dependent or p53-independent function. This reinforces our belief that miR-125b has potential as a therapeutic target for the management of patients with metastatic prostate cancer.

【 授权许可】

CC BY