iPLA2β-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment

Abstract

Group VIA phospholipase A2 (iPLA2β) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2β-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3–5 weeks of age (12–13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1β, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2β deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2β inhibition in HCC treatment.

Toward a New Era in the Management of Hepatocellular Carcinoma: Novel Perspectives on Therapeutic Options and Biomarkers

“…Many efforts have been devoted to unraveling the pathological mechanisms underlining the progression of chronic liver diseases to HCC, with the final aim being to find druggable targets to prevent or cure HCC. In this regard, the study of Andrade et al suggests that the inhibition of the group VIA phospholipase A2 (iPLA2β), a protein involved in the regulation of epithelial cells and macrophage functions, could prevent HCC by inducing cell-cycle arrest [6]. They demonstrated that iPLA2β KO mice have an improved resistance to diethylnitrosamine (DEN)-induced HCC that is likely to reside in the suppression of the hepatic expression of cyclin D2 (CCND2) and B-cell lymphoma 2 (BCL2), which are involved in cell-cycle regulation, and of IL6, IL10, and VCAM-1, which are involved in inflammatory processes.…”