Department of General Surgery, Cao County People's Hospital, Heze, Shandong Province 274400, China.
Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China.
Gene. 2019 Jul 30;707:78-85. doi: 10.1016/j.gene.2019.05.015. Epub 2019 May 7.
Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed miR-613 expression was downregulated in both chemoresistant and recurrent HCC patients. A remarkable decrease in miR-613 was detected in CD24 or OV6-positive liver CSCs and CSC-enriched hepatoma spheres. Down-regulation of miR-613 facilitated liver CSCs expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, bioinformatic and luciferase reporter analysis identified SOX9 as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of SOX9 in HCC cells. Special SOX9 siRNA abolished the discrepancy in liver CSCs proportion and the self-renewal capacity between miR-613 overexpression hepatoma cells and control cells, which further confirmed that SOX9 was required in miR-613-inhibited liver CSCs expansion. Furthermore, hepatoma cells with miR-613 overexpression performed more sensitivity to cisplatin or sorafenib treatment. Conclusion: miR-613 could inhibit HCC cell dedifferentiation and liver CSCs expansion by targeting SOX9 signaling and may prove to be a novel therapeutic target for HCC patients.
肝癌干细胞（CSCs）促进肝癌的发生、进展、耐药和复发。然而，CSC 增殖的潜在机制仍不清楚。在此，我们观察到耐药和复发的 HCC 患者中 miR-613 的表达均下调。在 CD24 或 OV6 阳性的肝 CSCs 和 CSC 富集的肝癌球体中，miR-613 的表达显著降低。miR-613 的下调通过促进肝癌细胞去分化和增强肝 CSCs 的自我更新来促进肝 CSCs 的扩增。机制上，生物信息学和荧光素酶报告分析鉴定 SOX9 是 miR-613 的直接靶标。miR-613 的过表达抑制了 HCC 细胞中 SOX9 的表达。特异性 SOX9 siRNA 消除了 miR-613 过表达肝癌细胞和对照细胞中肝 CSCs 比例和自我更新能力的差异，这进一步证实了 SOX9 在 miR-613 抑制肝 CSCs 扩增中是必需的。此外，过表达 miR-613 的肝癌细胞对顺铂或索拉非尼治疗更敏感。结论：miR-613 通过靶向 SOX9 信号抑制 HCC 细胞去分化和肝 CSCs 扩增，可能成为 HCC 患者的一种新的治疗靶点。
