Loss of Hepatocyte PI3Ka Protects Mice from Hepatocellular Carcinoma in association with altered lipid metabolism gene expression

Hepatocellular Carcinoma (HCC) is a disease with an increasing incidence and a high mortality rate; therefore, targeted therapies for HCC are urgently needed. PI3K-AKT-mTORC1 signaling is frequently induced in solid tumors and is associated with tumor progression and with the most aggressive type of HCC. However, complete inhibition of all PI3K isoforms is unlikely to achieve a favorable therapeutic index for HCC treatment due to on-target side effects. Here, we investigate the role of hepatocyte PI3Ka in HCC using conditional knockout mice. We found that PI3Ka in the hepatocyte is dispensable for AKT phosphorylation in HCC and in normal liver, and hepatocytes during compensatory proliferation following administration of the hepatocarcinogen. We have also found that AKT phosphorylation induced by hepatocyte growth factor (HGF) and epidermal growth factor (EGF) is mediated by redundant PI3Ka and PI3Kb activities. Nonetheless, mice lacking hepatocyte PI3Ka showed reduced HCC proliferation and reduced hepatocyte proliferation induced by DEN. This phenotype was associated with a gene expression signature indicating altered lipid metabolism and reduced formation of lipid droplets. Together, these results indicate that PI3Ka is a promising target for the treatment of HCC.