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

Abstract

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.

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…Low levels of ARF in prostate cancer (19 -21) were also attributed to androgen-inducible microRNA-125b that negatively regulates ARF in prostate cancer (68). Our studies suggest that low levels of ARF in prostate cancer increase the levels of MAGE-A11 by decreasing MAGE-A11 degradation.…”

MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells

“…An example for this may be the apoptotic cell death and p53 networks, which have been shown to be targeted by miR-125b on different levels. 7,21,25,39,40 Accordingly, our data reveal miR-125b-mediated suppression of pro-apoptotic genes Bak1 and Trp53inp1, as well as slightly reduced expression, albeit either not statistically significant or not within our cutoff criteria, in pro-apoptotic Bmf and Bbc3 (BCL2-binding component 3; Puma). Moreover, TNFAIP3, which has been shown to regulate apoptosis under low-serum conditions, was strongly decreased.…”

MicroRNA-125b targeted STAT3 to inhibit laryngeal squamous cell carcinoma cell growth and motility

“…miR-125b has been observed to be downregulated in various types of cancer, including oral cancer (23), bladder cancer (18), liver cancer (19), osteosarcoma (20) and endometrial cancer (24). Previous studies have also demonstrated that miR-125b was upregulated in a number of types of cancer, including prostate cancer (25), glioblastoma (26) and pediatric acute promyelocytic leukemia (27). However, there are no studies investigating the expression of miR-125b in LSCC.…”