MMP1型
癌症研究
基因敲除
肝细胞癌
细胞生长
医学
肿瘤进展
生物
癌症
内科学
基因表达
基因
遗传学
作者
Eun-Jeong Kim,Donghyo Kim,Jeon-Soo Lee,Jeehyun Yoe,Jong-Min Park,Chang‐Jin Kim,Dongjun Jeong,Sanguk Kim,Yoontae Lee
出处
期刊:Hepatology
[Wiley]
日期:2018-04-19
卷期号:67 (6): 2287-2301
被引量:67
摘要
Hepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signaling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor, Capicua (CIC), as a suppressor of HCC progression and a potential therapeutic target. Expression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. Levels of polyoma enhancer activator 3 (PEA3) group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETS translocation variant 4 (ETV4) is the most significantly up-regulated in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, it induces expression of matrix metalloproteinase 1 (MMP1), the MMP gene highly relevant to HCC progression, in HCC cells; and knockdown of MMP1 completely blocks the CIC deficiency-induced HCC cell proliferation and invasion.Our study demonstrates that the CIC-ETV4-MMP1 axis is a regulatory module controlling HCC progression. (Hepatology 2018;67:2287-2301).
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