Oxidative Stress/FOXO Pathway is Enhanced in Hepatocellular Carcinoma by Interferon α-2b Treatment Favoring Cellular Apoptosis and Slowing Down Oncogenesis

The deregulation of Wnt/Frizzled-mediated signaling pathway has been suggested to play a central role in hepatic carcinogenesis. The impaired expression of the Wnt/β-catenin signaling constituents caused a deviant activation of the signaling in hepatocellular carcinoma (HCC). This conduces to the activation of the β-catenin/TCF dependent target genes, that control cell proliferation, cell cycle, apoptosis or motility. Disruption of this cascade has been shown to display anti-cancer properties in HCC.

Forkhead box O-class 3a (FoxO3a) is a member of the FOXO family of transcription factors, which is found in adult liver and regulates the expression of genes implied in apoptosis. FoxO3a is post-translationally regulated, in a negative way by PI3K/Akt and MAPK/Erk and in a positive way by oxidative stress/JNK pathways.

Data from our laboratory, allow us to propose a model in which Interferon α-2b (IFN α- 2b) offers a connection between Wnt signaling pathways and the oxidative stress/FOXO pathway. Treatment with IFN α-2b cause an oxidative stress that could fortified the relationship between FOXO and β-catenin and might inhibit the interaction with TCF. The impairment on the formation of β-catenin/TCF4/ complexes could have a decisive role in decelerating the oncogenesis process. The clinical implications of these results are significant, because β-catenin, TCF, and FOXO turn out as molecular targets for new treatments which can alter their interactions privileging programmed cell death or apoptosis over proliferation in patients that suffer a potential hepatocarcinogenic trauma.

Keywords: AKT, chemical hepatocarcinogenesis, ERK, hepatocarcinoma cell lines, Hepatocellular carcinoma, Interferon α-2b, JNK, ROS, Smads, TFG-β, Wnt- βcatenin; FOXO.