Abstract 525: Role of a novel microRNA gene at frequently deleted chromosome 8p region in prostate cancer

Abstract

Abstract A frequent alteration in the prostate oncogenome is the loss of chromosome (chr) 8p21-22 region that has been traditionally associated with the loss of homeodomain protein, NKX3.1, that plays important roles in prostate cancer (PCa) initiation. Genomic deletions of this region increase significantly with tumor grade and are associated with poor prognosis in prostate cancer suggesting a link of this region with PCa progression. We proposed and validated a novel, paradigm shifting hypothesis that this frequently deleted locus is associated with a cluster of miRNA genes - miR-3622a/b and miR-383- that are lost in PCa and play an important mechanistic role in PCa progression and metastasis by regulating Epithelial-mesenchymal transition (EMT) and stemness. Extending our hypothesis, in this study, we evaluated the role of another miRNA gene located within this region- miR-4288- in prostate cancer. To understand the role of miR-4288 in prostate cancer, we performed miRNA expression profiling in laser capture microdissected (LCM) PCa tissues (n=64) and matched adjacent normal regions by real-time PCR. miR-4288 expression was down regulated in ~66% of tissue samples. miR-4288 expression was not altered significantly in 14% cases and high miR-4288 expression was observed in 20% cases. We performed ROC (Receiver Operating Characteristic) analyses to test the diagnostic potential of miR-4288 expression. Our analyses showed that miR-4288 expression can be a significant parameter to discriminate between normal and tumor tissues with an area under the ROC curve (AUC) of 0.711 (95% CI: 0.625-0.787, P<0.0001). We found that miR-4288 exhibits 81.54% sensitivity and 51% specificity as a diagnostic parameter. Association with clinicopathological parameters of the disease showed that miR-4288 expression was not significantly correlated with age, tumor stage, Gleason grade, biochemical recurrence or serum PSA levels. However, significant correlation was observed between miR-4288 expression and race. Analyses of miR-4288 expression in prostate cell lines showed that its expression is specifically attenuated in PCa cell lines compared to normal or immortalized prostate epithelial cells. To evaluate the functional role of miR-4288 in prostate cancer, miR-4288 precursor was overexpressed in PCa cell lines followed by functional assays. miR-4288 overexpression in PC3 and LNCaP cell lines led to decreased cellular viabilities as compared to control cells. Our preliminary data suggests that miR-4288 overexpression lead to morphological changes in these cell lines consistent with mesenchymal to epithelial transition (MET). In conclusion, our data suggests that miR-4288 is commonly downregulated in prostate cancer and plays an important regulatory role. Citation Format: Divya Bhagirath, Thao Yang, Shahana Majid, Varahram Shahryari, Soichiro Yamamura, Z. Laura Tabatabai, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. Role of a novel microRNA gene at frequently deleted chromosome 8p region in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 525.