Modulation of MSH2 gene expression and DNA global methylation in diethyl-nitrosamine induced hepatic fibrosis mouse model by cisplatin- anthocyanins combination

Novel therapeutic approaches targeting the molecular pathways of hepatocellular carcinoma (HCC) development are highly demanded. We aimed at studying the effect of cisplatin alone and combined with cranberry extract on global DNA methylation and the MSH2 gene expression in diethyl-nitrosamine (DEN)-induced hepatic fibrosis model, as a landmark in HCC development pathway in mice. Forty male albino mice were divided into 2 groups: Group I (n=10): control, Group II (n=30): mice were injected intraperitoneal with DEN and sub-classified into 3 equal groups; IIa: untreated, IIb: intraperitoneal cisplatin, IIc: intraperitoneal cisplatin + oral cranberry-derived anthocyanin. Histopathological examination of liver, assessment of global DNA methylation and MSH2 gene expression were done. MSH2 gene expression was significantly decreased in DEN-group as compared to the control group, but significantly increased by cisplatin alone and furthermore when anthocyanin was added (p<0.001). Global DNA methylation significantly increased in DEN-group, significant decrease in cisplatin-group and further decrease when anthocyanin was added (p<0.001). A significant negative correlation was observed between global DNA methylation and MSH2 gene expression among all the studied groups (p<0.001). Histopathological examination showed improvement of liver fibrosis when anthocyanin was added to cisplatin. Improvement of histopathological findings of DEN-induced hepatic fibrosis by cranberry-derived anthocyanins was associated with global DNA hypomethylation and increased MSH2 expression. Further studies are warranted to confirm the applicability of adding anthocyanins to liver fibrosis and HCC treatment regimen.