Jiang Xiang, Liu Yingyi, Wang Ganggang, Yao Ye, Mei Chengjie, Wu Xiaoling, Ma Weijie, Yuan Yufeng
Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University Wuhan 430071, Hubei, PR China.
Research Center of Digestive Diseases, Zhongnan Hospital of Wuhan University Wuhan 430071, PR China.
Am J Cancer Res. 2020 Aug 1;10(8):2355-2370. eCollection 2020.
Hepatocellular carcinoma (HCC) is leading cause of tumor-related deaths worldwide. The intracellular chloride channel protein (CLIC1) plays a role in the occurrence and progression of HCC, although the underlying mechanisms are still unclear. We evaluated the CLIC1 mRNA and protein levels in both patient tissues and HCC cell lines, and analyzed the correlation between CLIC1 expression and clinical features. The biological function of CLIC1 in HCC was examined in vivo and in vitro. The upstream regulatory factors were identified by bioinformatics programs, and downstream mechanisms affecting HCC behavior have also been explored and validated. CLIC1 was up-regulated in HCC tissues and cell lines, and promoted the proliferation, invasion and migration of HCC cells in vivo and in vitro. TP53 was identified as the upstream transcription factor of CLIC1. MiR-122-5p also regulated CLIC1 levels by degrading the transcripts. More importantly, we found that the increased CLIC1 was significantly related to the activation of MYC signaling. By binding with MYC, CLIC1 enhanced the transcription activity of MYC to downstream genes, rather than by altering its expression. Finally, a positive feedback regulatory loop between CLIC1 and MYC was established. CLIC1 is closely related to the occurrence, progression and prognosis of HCC, and a promising novel therapeutic target.
肝细胞癌（HCC）是全球肿瘤相关死亡的主要原因。细胞内氯离子通道蛋白（CLIC1）在HCC的发生和发展中起作用，但其潜在机制仍不清楚。我们评估了患者组织和HCC细胞系中CLIC1的mRNA和蛋白水平，并分析了CLIC1表达与临床特征之间的相关性。在体内和体外研究了CLIC1在HCC中的生物学功能。通过生物信息学程序鉴定了上游调节因子，并对影响HCC行为的下游机制进行了探索和验证。CLIC1在HCC组织和细胞系中上调，并在体内和体外促进HCC细胞的增殖、侵袭和迁移。TP53被鉴定为CLIC1的上游转录因子。MiR-122-5p也通过降解转录本来调节CLIC1水平。更重要的是，我们发现CLIC1的增加与MYC信号通路的激活显著相关。通过与MYC结合，CLIC1增强了MYC对下游基因的转录活性，而不是通过改变其表达。最后，建立了CLIC1与MYC之间的正反馈调节环。CLIC1与HCC的发生、发展和预后密切相关，是一个有前景的新型治疗靶点。
