Xu Yunxiuxiu, Lai Yu, Weng Hanqin, Tan Lanping, Li Yanshan, Chen Guangcheng, Luo Xingxi, Ye Yibiao
Department of Hepato-Billiary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Aging (Albany NY). 2019 May 5;11(9):2551-2564. doi: 10.18632/aging.101876.
Drug resistance is still a major obstacle for efficient treatment of hepatocellular carcinoma (HCC) during the cisplatin-based chemotherapy. Recent studies have demonstrated that CD133 positive population of cancer cells are responsible for multiple drug resistance. We are supposed to take strategies to sensitize CD133 HCC cells to cisplatin treatment. In the present study, CD133 HCC cells showed significant cisplatin-resistance compared to the CD133 HCC cells. Downregulation of miR-124 was observed in CD133 HCC cells. However, enforced expression of miR-124 can increase the sensitivity of CD133 HCC cells to cisplatin treatment in vitro and in vivo. Mechanically, overexpression of miR-124 was found to inhibit the expression of SIRT1 and thus promoted the generation of ROS and phosphorylation of JNK. As the results, overexpression of miR-124 expanded the apoptosis in cisplatin-treated CD133 HCC cells. We then demonstrated that overexpression of miR-124 sensitized cisplatin-induced cytotoxicity against CD133 hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway.
在基于顺铂的化疗过程中，耐药性仍是肝细胞癌（HCC）有效治疗的主要障碍。最近的研究表明，癌细胞中CD133阳性群体与多药耐药有关。我们应该采取策略使CD133肝癌细胞对顺铂治疗敏感。在本研究中，与CD133阴性肝癌细胞相比，CD133阳性肝癌细胞表现出显著的顺铂耐药性。在CD133阳性肝癌细胞中观察到miR-124表达下调。然而，miR-124的强制表达可在体外和体内增加CD133阳性肝癌细胞对顺铂治疗的敏感性。从机制上讲，发现miR-124的过表达抑制了SIRT1的表达，从而促进了ROS的产生和JNK的磷酸化。结果，miR-124的过表达扩大了顺铂处理的CD133阳性肝癌细胞中的凋亡。然后我们证明，miR-124的过表达通过靶向SIRT1/ROS/JNK途径使顺铂诱导的对CD133阳性肝细胞癌细胞的细胞毒性敏感。
