Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians
Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians
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DOI：
10.18632/oncotarget.14198
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发表时间：
2017-01-31
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影响因子：
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通讯作者：
Dahiya, Rajvir
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作者：
Shiina, Marisa;Hashimoto, Yutaka;Dahiya, Rajvir
非洲裔美国人被诊断出患有更具侵袭性的前列腺癌，并且比白人的生存率更差，但是对这种健康差异的全面理解仍然不清楚。为了阐明导致这种差异的机制，我们分析了miR-34 b表达在非洲裔美国人和高加索人中的潜在参与。miR-34 b作为肿瘤抑制因子发挥作用，并通过调节细胞增殖、细胞周期和凋亡而具有多功能作用。我们发现，与高加索人相比，非裔美国人的人前列腺癌组织中miR-34 b的表达较低。与正常样本相比，前列腺癌中miR-34 b-3 p启动子区域的DNA超甲基化显示出显著更高的甲基化。然后，我们对miR-34 b-3 p的启动子区域进行测序，并在非洲裔美国人前列腺癌细胞系（MDAPCA-2b）中发现miR-34 b的染色体缺失，而在高加索人细胞系（DU-145）中没有发现。我们发现，AR和ETV 1基因在MDA-PCa-2b和DU-145细胞中在过表达miR-34 b后差异表达。通过荧光素酶报告基因分析验证miR-34 b与AR和ETV 1的3'非翻译区的直接相互作用。我们发现，在非洲裔美国人中，miR-34 b下调与导致细胞增殖增加的高AR水平呈负相关。与高加索细胞系（DU-145）相比，在细胞系中过表达miR-34 b在非洲裔美国人细胞（MDA-PCa- 2b）中显示出更高的细胞增殖抑制、凋亡和G1期阻滞。总之，我们的研究结果表明，miR-34 b和AR的差异表达与非洲裔美国人的前列腺癌侵袭性相关。
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 (MDAPCA-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.