Clinical and biological significance of miR-23b and miR-193a in human hepatocellular carcinoma.
Clinical and biological significance of miR-23b and miR-193a in human hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.14332
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发表时间：
2017-01-24
期刊：
影响因子：
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通讯作者：
Salvi A
中科院分区：
文献类型：
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作者：
Grossi I;Arici B;Portolani N;De Petro G;Salvi A
肝细胞癌（HCC）是最常见的肝癌，预后极差。microRNA（miRs）的失调确实与HCC的发生和进展有关。在这项研究中，我们评估了miR-23 b和miR-193 a在59和67例HCC患者中的表达。miR-23 b和miR-193 a在原发性HCC中的表达显著下调。此外，miR-193 a表达较高的患者表现出较长的OS和DFS，表明miR-193 a可能是HCC患者的分子预后因子。由于人类癌症中可能存在DNA甲基化对miR的调控，因此我们验证了HCC组织中miR-23 b和miR-193 a的下调是否与DNA甲基化有关。观察到miR-23 b表达和DNA甲基化之间的相反趋势，表明miR-23 b可以被表观遗传学调控。相反，miR-193 a的下调不是由DNA甲基化介导的。为了验证miR-23 b和miR-193 a作为体外反应性分子靶点的潜在作用，我们使用DNA甲基化抑制剂5-aza-dC来恢复miR-23 b表达水平并联合miR-193 a转染。联合处理导致细胞增殖和迁移的显著抑制。综上所述，我们的研究结果提供了证据，证明miR-23 b和miR-193 a可能是HCC的分子诊断和预后因素;此外，miR-23 b和miR-193 a是与表观遗传药物5-aza-dC联合限制HCC细胞侵袭性的反应性分子靶标。此外，我们的研究结果为HCC中这些miR的表观遗传调控提供了新的进展。
Hepatocellular carcinoma (HCC) is the most common cancer of the liver with a very poor prognosis. The dysregulation of microRNAs (miRs) is indeed implicated in HCC onset and progression. In this study, we have evaluated the expression of miR-23b and miR-193a in a large cohort of 59 and 67 HCC patients, respectively. miR-23b and miR-193a resulted significantly down-regulated in primary HCCs compared to their matched peritumoral counterparts. Furthermore, patients with higher miR-193a expression exhibited longer OS and DFS, suggesting that miR-193a may be a molecular prognostic factor for HCC patients. Since the regulation of miRs by DNA methylation may occur in human cancers, we verified whether the down-modulation of miR-23b and miR-193a in HCC tissues could be related to DNA methylation. An inverse trend between miR-23b expression and DNA methylation was observed, indicating that miR-23b can be epigenetically regulated. By contrast, the down-regulation of miR-193a was not mediated by DNA methylation. To verify the potential role of miR-23b and miR-193a as responsive molecular targets in vitro, we used the inhibitor of DNA methylation 5-aza-dC to restore miR-23b expression level in combination with miR-193a transfection. The combined treatment led to a significant inhibition of cellular proliferation and migration. Taken together, our findings provide evidence that miR-23b and miR-193a may be molecular diagnostic and prognostic factors for HCC; furthermore, miR-23b and miR-193a are responsive molecular targets for limiting HCC cell aggressiveness in combination with the epigenetic drug 5-aza-dC. Moreover, our results provide new advances in the epigenetic regulation of these miRs in HCC.