Arsenic is a well known environmental hazardous material, chronic arsenic exposure results in different types of liver damage. Among them, liver fibrosis has become a research hotspot because of its reversibility, while the underlying mechanism is still unclear. Previous studies revealed that EGFR/ERK signaling appears to play an important role in fibrosis diseases. In this study, sprague-dawley rats were exposed to different doses of arsenite for 36 weeks to investigate the roles of EGFR/ERK signaling on arsenite-induced liver fibrogenesis. Our results showed that long-term arsenite exposure induced liver fibrosis, accompanied by hepatic stellate cells (HSCs) activation, excessive serum secretion of extracellular matrix (ECM), and hepatocytes epithelial-mesenchymal transformation (EMT). In addition, arsenite exposure caused hyperphosphorylation of EGFR/ERK signaling in liver tissue of rats, indicating that EGFR/ERK signaling may be involved in arsenite-induced liver fibrosis. Indeed, erlotinib (a specific phosphorylation inhibitor of EGFR) intervention significantly decreased arsenite induced hyperphosphorylation of EGFR/ERK signaling, thereby suppressed hepatocytes EMT process and alleviated liver fibrogenesis in arsenite exposed rats. In summary, the present study provides evidences showing that hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes EMT and liver fibrosis in rats, which brings new insights into the pathogenesis of arsenic-induced liver injury.

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.