{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:35:24Z","timestamp":1785929724131,"version":"3.56.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1826,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Activation of \u03b2-catenin, the central effector of the canonical Wnt pathway and a recognized oncogene, has been implicated in hepatocellular carcinoma. We examined<\/jats:bold>\n                                 <jats:bold>\n                                    N\n                                 <\/jats:bold>\n                                 <jats:bold>-nitrosodiethylamine (DEN)-induced tumorigenesis in hepatic \u03b2-catenin conditional knockout mice (\u03b2-cat KO). Male \u03b2-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<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>tumor intervention studies, specific inhibitors were administered intraperitoneally or through drinking water. Intriguingly, \u03b2-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 \u03b1 (PDGFR\u03b1)\/phosphoinositide 3-kinase (PIK3CA)\/Akt activation and c-Myc overexpression.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>suppression of \u03b2-catenin expression in hepatoma cells led to enhanced PDGFR\u03b1 expression, which was abrogated in the presence of nuclear factor \u03baB (NF-\u03baB) inhibitor. Daily treatment of 6-month-old DEN-exposed \u03b2-cat KO with PDGFR\u03b1 inhibitor dramatically reduced tumor numbers and size. Inclusion of<\/jats:bold>\n                                 <jats:bold>\n                                    N\n                                 <\/jats:bold>\n                                 <jats:bold>-acetyl-L-cysteine, a known antioxidant and NF-\u03baB inhibitor, in the drinking water led to complete abolition of tumorigenesis in DEN-exposed \u03b2-cat KO.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion:<\/jats:title>\n            <jats:p>\n                                 <jats:bold>Loss of \u03b2-catenin impairs the liver's ability to counteract DEN-induced oxidative stress and enhances tumorigenesis through PDGFR\u03b1\/PIK3CA\/Akt signaling. Blockade of PDGFR\u03b1 or oxidative stress dramatically affects \u03b2-catenin\u2013deficient tumorigenesis. Also, hepatoma cells use PDGFR\u03b1\/PIK3CA signaling as an escape mechanism following \u03b2-catenin suppression, and their sequential suppression profoundly impedes tumor proliferation.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.23747","type":"journal-article","created":{"date-parts":[[2010,6,15]],"date-time":"2010-06-15T15:32:16Z","timestamp":1276615936000},"page":"954-965","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":83,"title":["Conditional \u03b2-Catenin Loss in Mice Promotes Chemical Hepatocarcinogenesis: Role of Oxidative Stress and Platelet-Derived Growth Factor Receptor \u03b1\/Phosphoinositide 3-Kinase Signaling\u2020"],"prefix":"10.1097","volume":"52","author":[{"given":"Xu-Feng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalea","family":"Misse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sucha","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngsoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satdarshan P. 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