Abstract A079: MicroRNA-139 regulates prostate cancer aggressiveness by targeting IGF1R
Authors: Amemiya Yutaka , Wallis Christopher J. , Benatar Tania , Kobylecky Elizabeth , Sugar Linda , Sherman Christopher , Nam Robert , Seth Arun K. 
Published: February 2019

Background: Dysregulated microRNA (miRNA) expression has been implicated in prostate cancer progression. We previously identified a panel of five miRNAs associated with biochemical recurrence and metastasis following prostatectomy based on NGS-based whole miRNome discovery and qPCR-based validation analysis. In this analysis, we examine the effect of miR-139-5p, one of the downregulated miRNAs identified in the panel, in greater detail.

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 for functional assays. Finally, we examined pathways through which miR-139 may function using prediction algorithms and confirmed targets by Western blotting and reporter assays.

Results: MiR-139 downregulation was significantly associated with a variety of accepted prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis was significantly lower among patients with high miR-139 expression (p=0.0004 and 0.038, respectively). After adjusting for known prognostic factors, patients with high miR-139 expression had significantly lower risk of recurrence (HR 0.77, 95% 0.58-1.04). Validation in the TCGA dataset showed a significant association between dichotomized miR-139 expression and biochemical recurrence (OR 0.52, 95% CI 0.33-0.82). Overexpression of miR-139 in PC3 and DU145 prostate cancer cells led to a significant reduction in cell proliferation and migration compared to control cells. IGF1R was identified as a potential target of miR-139 based on previous work in colorectal and non-small cell lung cancers. Reduced luciferase reporter activity was observed upon co-transfection of the 3′ UTR of IGF1Rβ with miR-139 mimic compared to co-transfection with control mimic. Furthermore, Western blotting of PC3 cells overexpressing miR-139 revealed reduced IGF1Rβ protein expression, as well as reduced expression of its downstream pathway proteins pAKT and pERK. Cell cycle analysis indicated a significantly increased number of cells arrested in G2/M phase in PC3 cells overexpressing miR-139. This was accompanied by an increase in β-galactosidase stained senescent cells and p21 protein expression.

Conclusions: miR-139 is associated with improved prognosis in patients with localized prostate cancer. This appears to be mediated through an IGF1R pathway leading to increased p21 expression, resulting in prostate cancer cell senescence from G2 arrest.

Citation Format: Yutaka Amemiya, Christopher J. Wallis, Tania Benatar, Elizabeth Kobylecky, Linda Sugar, Christopher Sherman, Robert Nam, Arun K. Seth. MicroRNA-139 regulates prostate cancer aggressiveness by targeting IGF1R [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A079.