Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China.
Department of General Surgery, Cao County People's Hospital, Heze, Shandong province, 274400, China.
Exp Cell Res. 2020 Sep 15;394(2):112162. doi: 10.1016/j.yexcr.2020.112162. Epub 2020 Jul 5.
Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for liver CSCs expansion remains unclear. Herein, we report that miR-124 is downregulated in liver CSCs and associated with the poor prognosis of HCC. Functional studies revealed that a forced expression of miR-124 inhibits liver CSCs self-renew and tumorigenesis. Conversely, miR-124 knockdown promotes liver CSCs self-renew and tumorigenesis. Mechanistically, miR-124 directly target Caveolin-1 (CAV1) via its mRNA 3'UTR in liver CSCs. Furthermore, miR-124 expression determines the responses of hepatoma cells to sorafenib treatment. The analysis of patient cohort and patient-derived xenografts (PDXs) further demonstrated that miR-124 may predict sorafenib benefits in HCC patients. In conclusion, our findings revealed the crucial role of the miR-124 in liver CSCs expansion and sorafenib response, rendering miR-124 an optimal target for the prevention and intervention in HCC.
肝癌干细胞（CSCs）促进肝癌的发生、进展、复发和耐药。然而，CSCs 扩增的潜在机制尚不清楚。在此，我们报告 miR-124 在 CSCs 中下调，并与 HCC 的不良预后相关。功能研究表明，miR-124 的强制表达抑制 CSCs 的自我更新和致瘤性。相反，miR-124 的敲低促进 CSCs 的自我更新和致瘤性。机制上，miR-124 通过其在 CSCs 中的 mRNA 3'UTR 直接靶向窖蛋白 1（CAV1）。此外，miR-124 的表达决定了肝癌细胞对索拉非尼治疗的反应。对患者队列和患者来源的异种移植瘤（PDXs）的分析进一步表明，miR-124 可能预测 HCC 患者对索拉非尼的获益。总之，我们的研究结果揭示了 miR-124 在 CSCs 扩增和索拉非尼反应中的关键作用，使其成为预防和干预 HCC 的理想靶点。
