Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians

// Marisa Shiina 1, * , Yutaka Hashimoto 1, * , Taku Kato 1 , Soichiro Yamamura 1 , Yuichiro Tanaka 1 , Shahana Majid 1 , Sharanjot Saini 1 , Shahryari Varahram 1 , Priyanka Kulkarni 1 , Pritha Dasgupta 1 , Yozo Mitsui 1 , Mitsuho Sumida 1 , Laura Tabatabai 1 , Guoren Deng 1 , Deepak Kumar 2 , Rajvir Dahiya 1 1 Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California, USA 2 Division of Science and Mathematic, Cancer Research Laboratory, University of the District of Columbia, Washington, DC, USA * These authors have contributed equally to this work Correspondence to: Rajvir Dahiya, email: rdahiya@ucsf.edu Keywords: miR-34b, prostate cancer, african-americans, caucasians, androgen receptor Received: October 04, 2016      Accepted: November 23, 2016      Published: December 25, 2016 ABSTRACT African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. miR-34b functions as a tumor suppressor and has a multi-functional role, through regulation of cell proliferation, cell cycle and apoptosis. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal samples. We then sequenced the promoter region of miR-34b-3p and found a chromosomal deletion in miR-34b in African-American prostate cancer cell line (MDA-PCA-2b) and not in Caucasian cell line (DU-145). We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in the African-American cells (MDA-PCa-2b) compared to Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans.