Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer.
OBJECTIVE
Previously, we showed that activation of the beta-catenin/Wnt pathway is a dominant event during c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs displayed nuclear accumulation of beta-catenin in the absence of beta-catenin mutations, suggesting that alterations in other members of the Wnt pathway might be responsible for nuclear localization of beta-catenin. Here, we investigated the mechanisms responsible for nuclear translocation of wild-type beta-catenin and addressed the potential contribution of the Wnt pathway in c-Myc/E2F1 hepatocarcinogenesis.


METHODS
Status of the members of the Wnt pathway was determined through microsatellite and Western blot analysis.


RESULTS
Majority of c-Myc/E2F1 HCCs exhibited multiple abnormalities in the Wnt pathway regardless of the presence of beta-catenin mutations. The observed abnormalities included overexpression of Wnt-1, Frizzled 1 and 2 receptors, Dishevelled-1, downregulation of Secreted frizzled-related protein-1, GSK-3beta inactivation, microsatellite instability at the Axin locus as well as induction of beta-catenin target genes, such as glutamine synthetase, glutamate transporter-1, and Wisp-1. HCCs with beta-catenin activation displayed significantly higher proliferation rate and larger tumor size when compared with beta-catenin negative tumors.


CONCLUSIONS
The data demonstrate that multiple abnormalities in the members of the Wnt pathway lead to nuclear accumulation of beta-catenin and suggest that activation of Wnt pathway provides proliferative advantages in c-Myc/E2F1-driven hepatocarcinogenesis.
Calvisi
Diego F
DF
Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Building 37, Room 4146A, 37 Convent Drive MSC 4262, Bethesda, MD 20892-4262, USA.
Conner
Elizabeth A
EA
Ladu
Sara
S
Lemmer
Eric R
ER
Factor
Valentina M
VM
Thorgeirsson
Snorri S
SS
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D020869:Gene Expression Profiling; D016259:Genes, myc / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3