ARMCX3 mediates susceptibility to hepatic tumorigenesis promoted by dietary lipotoxicity.

Abstract

Abstract: ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in pa-tients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 in-validation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosa-mine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overex-pression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalida-tion promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosa-mine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 inter-action required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.