Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms

Akt is frequently hyperactivated in human cancers and is targeted for cancer therapy. However, the physiological consequences of systemic Akt isoform inhibition were not fully explored. We showed that while combined Akt1 and Akt3 deletion in adult mice is tolerated, combined Akt1 and Akt2 deletion induced rapid mortality. Akt2−/− mice survived hepatic Akt1 deletion but all developed spontaneous hepatocellular carcinoma (HCC), which is associated with FoxO-dependent liver injury and inflammation. The gene expression signature of HCC-bearing livers is similar to aggressive human HCC. Consistently, neither Akt1−/− nor Akt2−/− mice are resistant to diethylnitrosamine-induced hepatocarcinogenesis, and Akt2−/− mice display a high incidence of lung metastasis. Thus, in contrast to other cancers, hepatic Akt inhibition induces liver injury that could promote HCC. [Display omitted] •Early onset of HCC after hepatic deletion of Akt1 in Akt2−/− mice•The HCC is preceded by liver injury and inflammation in a FoxO1-dependent manner•Akt2 deficiency promotes lung metastasis after hepatocarcinogenesis•Akt is required for hepatic STAT5 phosphorylation and IGF1 expression Wang et al. show that systemic deletion of Akt1 and Akt2 is lethal while hepatic deletion leads to hepatocellular carcinoma (HCC) with complete penetrance in a FoxO1-dependent manner. Deletion of either Akt1 or Akt2 did not inhibit diethylnitrosamine-induced HCC, but Akt2 loss increased metastasis.