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.
