Functional And Molecular Mechanism Analysis Of Gpr110 In Carcinogen-induced Hepatocarcinogenesis

Hepatocarcinogenesis is a complex process,including pronounced necroinflammation,unregulated hepatocyte damage,subsequent extensive fibrosis and carcinogenesis.Hepatocellular carcinoma（HCC）is a cancer often associated with chronic tissue injury.Chronic liver injury,triggering perpetual hepatocellular damage,hepatocyte regeneration,and inflammation,is thought to be the established background which promotes neoplasia in these pathophysiologically distinct diseases.HCC has clearly defined etiological factors including viral hepatitis,nonalcoholic steatohepatitis（NASH）,alcoholic liver disease and cirrhosis.Cirrhosis,which develops from long period chronic liver disease,is considered as the primary risk factor leading to HCC.However,the molecular mechanisms responsible for this malignant transformation remains elusive.GPR110 belongs to members of adhesion G protein-coupled receptor family.It is an orphan receptor and highly conserved among species.Up to now,the physiological function of GPR110 remains largely unknown.Lum et al.have previously identified Gpr110 as a potential oncogene in murine T cell lymphomas during a large scale retroviral insertion mutagenesis screen.Subsequently,they detect overexpression of GPR110 transcript and protein in the majority of lung（74%）and prostate（59%）adenocarcinomas as well as related cell lines.Therefore,it can be speculated that GPR110 may participate in the development of tumor.However,the physiological functions of Gpr110 and the relationship between Gpr110 loss and hepatocarcinogenesis in vivo are still unknown.Here we used Gpr110 knockout mice to study the role of Gpr110 in hepatocarcinogenesis.We found deficiency of Gpr110 impeded diethylnitrosae（DEN）plus carbon tetrachloride（CCl₄）-induced HCC formation.Moreover,lack of Gpr110 mitigated CCl₄-mediated liver injury,hepatic fibrosis,and ultimately delayed the development of cirrhosis and progression into HCC.Molecular mechanisms underlying the phenotypes in Gpr110^-/-mice correlated with augmented activation of IL-6/STAT3 pathway which exerted hepatoprotective effects during liver damage,fibrosis and oncogenesis.Pharmacological inhibition of the activation of the IL-6/STAT3 pathway enhanced hepatic fibrosis and promoted DEN plus CCl₄-induced carcinogenesis in Gpr110^-/-mice.In summary,we generated the first Gpr110 knockout mouse model,and revealed that lacking of Gpr110 decelerates liver fibrosis/cirrhosis progressing into tumorgenesis,which is due to weakened liver injury and fibrosis caused by activation of IL-6/STAT3 pathway.All these results indicate that targeting of Gpr110 and activating of IL-6/STAT3 pathway might be potential therapeutic strategies for HCC patients.