Hepatic Activation of FOXO3 Is Associated with Pentose Phosphate Pathway Activation as Well as mTORC2-Akt Signaling and Enhances Oxidative Damage-Associated Hepatocellular Carcinogenesis

Abstract

Introduction: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Mutations are commonly found in the signaling regulating the Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of Akt signaling 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. Method: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed surgically resected HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form. Results: We observed that FOXO3 protein is overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 in mice 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 mTORC2-mediated Akt activation presumably in a cell-intrinsic manner. 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. On one side, FOXO3 supports in protecting from ROS and may avoid cellular crisis but FOXO3 can also promote ROS signaling on the other side and support hepatocellular carcinogenesis.