Hepatic activation of FOXO3 regulates mTORC2-Akt and enhances oxidative damage-associated hepatocellular carcinogenesis

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80 – 90% of cases. Mutations are commonly found in the signaling regulating the PI3K/Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of PI3K/Akt are members of the forkhead box O family (FOXO). FOXOs were initially considered as tumor suppressors by inducing cell cycle arrest and apoptosis. However, there is increasing evidence showing that FOXOs, especially FOXO3, can support tumorigenesis.