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

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.

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

“…MicroRNAs have been implicated in racial disparity in AAs when compared with Caucasians (9,(37)(38)(39). In this direction, Wang et al reported that AA-specific/-enriched miRNA-mRNA pairings such as miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2 and miR-34a/PPP2R2A may play a critical role in the activation of oncogenic pathways in AA PCa cells (39).…”

Lack of Racial Survival Differences in Metastatic Prostate Cancer in National Cancer Data Base (NCDB): A Different Finding Compared to Non-metastatic Disease

“…It is widely recognized that when compared to white men, African American men are more likely to develop PCa, tend to be diagnosed at a younger age, exhibit higher prostate-specific antigen (PSA) levels, and demonstrate more advanced or metastatic disease at diagnosis (8)(9)(10)(11)(12). Besides, African American men are four times more likely to develop metastatic PCa (mPCa) than white men and more than twice as likely to die from PCa (13)(14)(15)(16)(17)(18)(19). It is of vital importance to continue research on racial disparity of PCa to better understand the disease and improve the survival outcomes of African American men.…”

Coordinated AR and microRNA regulation in prostate cancer

“…Let-7c indirectly represses AR activity by targeting c-Myc, which acts as a transcription factor for the AR gene [ 65 , 66 ]; (B) AR mRNA—miRs target AR directly through binding to microRNA response elements in its transcript. Most microRNAs target the 3′UTR [ 4 , 24 , 31 , [38] , [39] , [40] , [41] , [42] , [43] , 45 , 46 ], but interactions with the coding region and 5′UTR have also been reported [ 4 , 56 ]; (C) AR-mediated transcription of target genes—miRs modulate AR indirectly by targeting cofactors, regulators or effectors of AR activity [ 19 , 63 , 64 ]; (D) AR competitive endogenous RNAs (ceRNAs) —AR is regulated by ceRNAs containing microRNA response elements (MREs) for AR-targeting miRs. For example, PlncRNA-1 protects AR from miR-mediated repression.…”