MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that miR-29a is downregulated in tumor-initiating cells (T-ICs) and has an important function in liver T-ICs. Functional studies revealed that miR-29a knockdown promotes liver T-ICs self-renewal and tumorigenesis. Conversely, a forced miR-29a expression inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, we find that miR-29a downregulates Bcl-2 via binding its mRNA 3'UTR in liver T-ICs. The correlation between miR-29a and Bcl-2 is validated in human HCC tissues. Furthermore, the miR-29a expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-29a high patients are more sensitive to sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-29a in liver T-ICs expansion and sorafenib response, rendering miR-29a as an optimal target for the prevention and intervention of HCC.

中文翻译：

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microRNA-29a通过Bcl-2途径调节肝癌起始细胞的扩增。

MicroRNA（miRNA）参与肝细胞癌（HCC）的肿瘤发生，进展，复发和耐药性。但是，很少有miRNA被鉴定并进入临床实践。在此，我们报道了miR-29a在肿瘤起始细胞（T-ICs）中被下调，并且在肝脏T-ICs中具有重要的功能。功能研究表明，miR-29a基因敲低可促进肝脏T-IC的自我更新和肿瘤发生。相反，miR-29a的强制表达抑制肝脏T-IC的自我更新和肿瘤发生。从机理上讲，我们发现miR-29a通过结合其mRNA在肝T-IC中的mRNA 3'UTR下调Bcl-2。miR-29a和Bcl-2之间的相关性已在人肝癌组织中得到验证。此外，miR-29a的表达决定了肝癌细胞对索拉非尼治疗的反应。对患者来源的异种移植物（PDXs）的分析进一步表明，miR-29a高患者对索拉非尼治疗更为敏感。总之，我们的发现揭示了miR-29a在肝T-ICs扩展和索拉非尼反应中的关键作用，使miR-29a成为预防和干预HCC的最佳靶标。