Inhibitory effect of hepatocarcinogenesis by increased glucosylceramide in Gba2 knockout mice

Background and aims: Glycosphingolipids are members of membrane lipids and distributed widely in eukaryotic cells and play roles in the regulation of immunity, inflammation, angiogenesis and tumor growth. Different studies have shown that administration of ß-glucosylceramide in vivo and in vitro suppressed tumor growth. The Gba2 knockout mice accumulate clearly the naturally occurring glucosylceramide in various tissues, including the liver.

Our aim was to investigate the role of hepatic increased glucosylceramide in the diethylnitrosamine-induced hepatocarcinogenesis model.

Methods: Groups of eight 9–10 month old Gba2 knockout and wildtype control mice were injected i.p. with 25ug/g DEN weekly over three months. The mice were scarified between 4 and 6 months. Histochemical and Biochemical analysis were performed. Different liver cytokine levels were measured using commercially available arrays.

Results: Gba2 knockout mice developed significantly less nodular/HCC formation compared to wildtype controls. Liver Alpha-1-Fetoprotein (AFP) expression was clearly lower in the Gba2 knockout mice compared to control groups. However more hepatocyte swelling, cytoplasmic vacuolization and increased ALT was seen in the Gba2 knockout mice. Various liver cytokines were more than 50% increased in the Gba2 knockout mice compared to control groups.

Conclusions: Glucosylceramide seems to affect the cytokine mediated pathway that leads to suppress hepatocarcinogenesis. These findings underline the potential role of glycosphingolipids in tumor growth and could lead to the conclusion that glucosylceramide or GBA2 inhibitors might open new therapeutic option for HCC.