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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.

SUBMITTER: Shiina M

PROVIDER: S-EPMC5352406 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Shiina Marisa M Hashimoto Yutaka Y Kato Taku T Yamamura Soichiro S Tanaka Yuichiro Y Majid Shahana S Saini Sharanjot S Varahram Shahryari S Kulkarni Priyanka P Dasgupta Pritha P Mitsui Yozo Y Sumida Mitsuho M Tabatabai Laura L Deng Guoren G Kumar Deepak D Dahiya Rajvir R

Oncotarget 20170101 5

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- ...[more]

PMID: 28039468

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Project description:Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1, ATR, POLQ, NEIL3, ERCC6, BRCA2, BRCA1, XPC, JAG1, RPA1, POLE, ATM, and LIG1 in African American men, and POLQ, NEIL3, POLB, BRCA2, EXO1, ERCC6, ATR, RBBP8, BRCA1, ATM, JAG1, XPC, and POLE in Caucasians. We found that 89% of tumors had at least one mutation in nucleotide excision repair pathway genes in African Americans, whereas >40% of tumors had mutations in base excision repair pathway genes in Caucasians. We further identified a marginal increase in mutation rate in tumors in African Americans with increasing age. Tumors in Caucasians did not show a correlation with age, but a progressive increase in the mutation rate was observed at higher Gleason scores. Our data reveal significant differences in the molecular signatures in the DNA repairome in prostate cancer between African Americans and Caucasians. These data also have substantial implications regarding the well-known health disparities in prostate cancer, such as the higher mortality in African Americans than Caucasians.

Dataset Information

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

Publications

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

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