高磷酸化
MAPK/ERK通路
亚砷酸盐
细胞生物学
表观遗传学
癌症研究
下调和上调
DNA甲基化
化学
信号转导
肝星状细胞
生物
磷酸化
基因表达
生物化学
砷
基因
内分泌学
有机化学
作者
Dapeng Wang,Wenli Ruan,Lili Fan,Huifen Xu,Qian Song,Heng Diao,Rui He,Ying Jin,Aihua Zhang
标识
DOI:10.1016/j.jhazmat.2022.129577
摘要
Arsenic is a widespread naturally contaminant. Previous studies have highlighted the issue of liver fibrosis induced by arsenic exposure, while the exact mechanisms are not yet fully understood. Recent studies suggest that Mig-6/EGFR/ERK signaling appear to play important roles in fibrosis caused by various factors. In this study, we focused on the epigenetic modification combined with the signaling dysregulation to validate the role of Mig-6 in regulating EGFR/ERK signaling in arsenite-induced human hepatic stellate cells (HSCs) activation. Our results revealed that arsenite exposure induced HSCs activation and extracellular matrix (ECM) deposition. The EGFR/ERK signaling was significantly hyperphosphorylated in arsenite-exposed HSCs, and Mig-6 inactivation was involved in arsenite induced hyperphosphorylation of EGFR and activation of HSCs. Additionally, we further illustrated that hypermethylation of Mig-6 gene promoter region was responsible for the downregulation of Mig-6 induced by arsenite exposure. Moreover, 5-Aza-dC (a DNA methyltransferase inhibitor) can efficiently rescue hypermethylation of Mig-6 gene, decrease the hyperphosphorylation of EGFR/ERK signaling, then reverse arsenite induced HSCs activation. Taken together, the present study strongly suggests that inactivating of Mig-6 function by hypermethylation of its promoter region leading to hyperphosphorylation of EGFR/ERK signaling, and is involved in arsenite-induced HSCs activation and ECM deposition.
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