MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

Abstract

Background: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next‐generation sequencing‐based whole miRNome sequencing and quantitative polymerase chain reaction‐based validation analysis. In this study, we examined the mechanism of action of miR‐139‐5p, one of the downregulated miRNAs identified in the panel. Methods: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR‐139 (dichotomized around the median) using the Kaplan‐Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR‐139 to confirm its targets as well as examine pathways through which miR‐139 may function using cell‐based assays. Results: Low miR‐139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR‐139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR‐139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR‐139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33‐0.82). Overexpression of miR‐139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR‐139 based on multiple miRNA‐binding sites in 3′‐untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR‐139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR‐139 treatment, which was reversed by the addition of miR‐139 antagomir. Examination of the molecular mechanism of growth inhibition by miR‐139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. Conclusions: miR‐139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.

MiR-139-5p influences hepatocellular carcinoma cell invasion and proliferation capacities via decreasing SLITRK4 expression

“…Usually, miRNAs can silence the target genes by post-transcriptional regulation by binding to the 3 untranslated region (UTR) of target genes [6], and dysregulation of the miRNAs has been proved to have significant correlation with tumor initiation, progression and metastasis [7][8][9][10]. MiR-139-5p, located on chromosome 11q13.4, takes part in many important signaling pathway and has been showed to play anti-oncogenic roles in many cancers [11][12][13][14]. Therefore, the dysregultion of miR-139-5p in HCC may also lead crucial outcomes in the progression of HCC.…”

miR‑139‑5p affects cell proliferation, migration and adipogenesis by targeting insulin‑like growth factor 1 receptor in hemangioma stem cells

“…For instance, cui et al (29) proved that miR-139 suppresses the generation and proliferation of β-casein by targeting IGF-1R in bovine mammary epithelial cells. Nam et al (30) confirmed that the overexpression of miR-139 may inhibit IGF-1R and ultimately inhibit the proliferation and migration of prostate cancer cells through the downstream effects of the PI3K/AKT pathway. However, to the best of our knowledge, there is no existing research on how miR-139-5p may affect the proliferation, differentiation and migration of HemScs.…”

Long non-coding RNA NEAT1 aggravates epilepsy and seizure-induced neuronal damage by regulating microRNA-139/ROCK1 axis

“…Using microarray analysis, we uncovered that NEAT1 might target miR-139 directly and dual luciferase reporter gene assay validated the findings. It has been uncovered that miR-139 dysregulation was connected with onset and progression of assorted malignancies such as prostate [27], hepatocellular [28], and hepatocellular cancer [29]. Besides, miR-139 was also found to partake in the inhibitory function of monomethyl fumarate which exerted on oxidative stress and inflammatory response in intracerebral hemorrhageinduced rat brain damage [30].…”