Oncogenic Akt-FOXO3 loop favors tumor-promoting modes and enhances oxidative damage-associated hepatocellular carcinogenesis

Background: 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. Methods: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form. Results: We found that FOXO3 protein is significantly overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 induced extensive hepatic damage and elevated gene expression of several HCC-associated factors. Furthermore, FOXO3 expression enhanced hepatotoxicin-induced tumorigenesis. Mechanistically, FOXO3 activation caused oxidative stress and DNA damage and triggered positive feedback-loop for Akt activation as well as mTORC2 activation. Interestingly, FOXO3 activated not only reactive oxygen species (ROS)-promoting pathways, but also ROS-eliminating systems, which can be associated with the activation of the pentose phosphate pathway. Conclusions: FOXO3 is a master regulator of ROS in a ‘carrot and stick’ manner; on one side avoiding cellular crisis while also supporting hepatocellular carcinogenesis. Clinically, we suggest analyzing FOXO3 activation status in patients with liver diseases, in addition to PI3K/Akt signaling. Personalized therapy of FOXO3 inhibition may be a reasonable, depending on the activation status of FOXO3.