Activation of β-catenin, the central effector of the canonical Wnt pathway and a recognized oncogene, has been implicated in hepatocellular carcinoma.We examined N-nitrosodiethylamine (DEN)-induced tumorigenesis in hepatic β-catenin conditional knockout mice (β-cat KO). Male β-cat KO and age- and sex-matched littermate controls were given a single intraperitoneal DEN injection and followed for 6-12 months for hepatic tumors. Hepatic tumors were characterized for histology, proliferation, apoptosis, oxidative stress, and specific proteins by way of western blot, immunohistochemistry, and coprecipitation studies. For in vivo tumor intervention studies, specific inhibitors were administered intraperitoneally or through drinking water. Intriguingly, β-cat KO mice showed a paradoxical increase in susceptibility to DEN-induced tumorigenesis. This accelerated tumorigenesis is due to increased injury and inflammation, unrestricted oxidative stress, fibrosis, and compensatory increase in hepatocyte proliferation secondary to platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PIK3CA)/Akt activation and c-Myc overexpression. In vitro suppression of β-catenin expression in hepatoma cells led to enhanced PDGFRα expression, which was abrogated in the presence of nuclear factor κB (NF-κB) inhibitor. Daily treatment of 6-month-old DEN-exposed β-cat KO with PDGFRα inhibitor dramatically reduced tumor numbers and size. Inclusion of N-acetyl-L-cysteine, a known antioxidant and NF-κB inhibitor, in the drinking water led to complete abolition of tumorigenesis in DEN-exposed β-cat KO. Conclusion: Loss of β-catenin impairs the liver's ability to counteract DEN-induced oxidative stress and enhances tumorigenesis through PDGFRα/ PIK3CA/Akt signaling. Blockade of PDGFRα or oxidative stress dramatically affects β-catenin - deficient tumorigenesis. Also, hepatoma cells use PDGFRα/PIK3CA signaling as an escape mechanism following β-catenin suppression, and their sequential suppression profoundly impedes tumor proliferation. (HEPATOLOGY 2010;52:954-965) Copyright © 2010 by the American Association for the Study of Liver Diseases.