Abstract 5445: Inhibition of tumor suppressor function of RUNX3 by miR-301a facilitates the progression of castration resistant prostate cancer

Abstract

Abstract Treatment of prostate cancer is still clinically challenging due to lack of reliable markers for diagnosis and prognosis. Serum prostate specific antigen (PSA) is of limited clinical utility due to poor sensitivity and specificity. A large number of false positives (50%) with traditional PSA testing lead many patients to undergoing unnecessary prostate biopsy and exposure to unnecessary risk of complications. So the goal of this study is to identify a reliable, non-invasive biomarker that can distinguish patients with benign, indolent and aggressive prostate cancer in various clinical settings. MicroRNAs (miRNAs) are small noncoding (18 to 28 nucleotides) RNA molecules that are present in all human cells, and their expression patterns are correlated with many cancer types, including CaP. In our results, we found a significant differential expression (p=0.013) of miR-301a in both tumor tissues (Gleason-6 and -7) and serum samples in comparison to benign prostatic hyperplasia (BPH) or adjacent benign samples. We observed a negative correlation between miR-301a and RUNX3 expression in human CaP samples suggesting tumor suppressive role RUNX3 might be compromised in CaP. To determine MiR-301a regulation on RUNX3, we evaluated miR-301a and RUNX3 protein in panel of prostate cancer cell lines, normal prostate epithelial cells and Benign Prostate Hyperplasia (BPH). Similar results such as inverse correlation between miR-301a and RUNX were found in cell culture models. Also, over expression of miR-301a down regulates RUNX3 activation in prostate cancer cell lines and silencing miR-301a expression reverts RUNX3 activation in BPH cells. While evaluating the reporter activity of RUNX3 either by co-transfecting with mimic or inhibitor of miR-301a in BPH and prostate cancer cells: over expression of miR-301a down regulated RUNX3 reporter activity which corresponded with RUNX3 protein expression. Similarly, silencing miR-301a reverted RUNX3 promoter activity and protein expression suggesting RUNX3 is a direct target of miR-301a in CaP cells. Silencing miR-301a reverted the pro-apoptotic function of RUNX3, results in reduced colony formation, adhesion, invasion and migration of CaP cells. Investigating the mechanistic link miR-301a and RUNX3 may explore whether it could facilitate clinical decision making such as the decision to proceed with early surgery rather than active surveillance for intermediate risk prostate cancer patients deemed to be at high risk of progression. Citation Format: Venkatesh Kolluru, Balaji Chandrasekhar, Collin McKenzie, Houda Alatassi, Murali Ankem, Chendil Damodaran. Inhibition of tumor suppressor function of RUNX3 by miR-301a facilitates the progression of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2017-5445