miR-124 regulates liver cancer stem cells expansion and sorafenib resistance
miR-124 regulates liver cancer stem cells expansion and sorafenib resistance
复制标题
miR-124调节肝癌干细胞扩增和索拉非尼耐药
DOI：
10.1016/j.yexcr.2020.112162
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发表时间：
2020-09-15
影响因子：
3.7
通讯作者：
Dong, Yuwei
中科院分区：
文献类型：
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作者：
Feng, Yun;Jiang, Weiliang;Dong, Yuwei
肝癌干细胞(CSCs)在肝细胞癌的发生、发展、复发和耐药中起重要作用。然而，肝脏CSCs扩张的潜在机制仍不清楚。在此，我们报告miR-124在肝脏CSCs中表达下调，并与肝细胞癌的不良预后相关。功能研究表明，miR-124的强制表达抑制了肝脏CSCs的自我更新和肿瘤的发生。相反，miR-124基因敲除促进肝脏CSCs自我更新和肿瘤发生。在机制上，miR-124通过其3‘端非编码区的mRNA直接靶向肝干细胞中的小窝蛋白-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物(PDX)的分析进一步表明，miR-124可以预测索拉非尼对肝细胞癌患者的益处。总之，我们的发现揭示了miR-124在肝脏CSCs扩张和索拉非尼反应中的关键作用，使miR-124成为预防和干预肝细胞癌的最佳靶点。
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.