Activation of beta-catenin provides proliferative and invasive advantages in c-myc/TGF-alpha hepatocarcinogenesis promoted by phenobarbital.
Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/transforming growth factor (TGF)-alpha transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring beta-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/beta-catenin signaling is involved in both anti-apoptotic and proliferative processes, we now have extended our analysis to investigate whether promotion by PB affects the occurrence of beta-catenin mutations in c-myc/TGF-alpha-driven tumors. The frequency of beta-catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF-alpha mice treated with PB (15/28; 53.6%) as compared with that in control HCCs (2/28; 7.1%). Furthermore, an intact beta-catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF-alpha untreated mice displayed loss of heterozygosity at the beta-catenin locus. Strikingly, in the majority of PB-treated HCCs beta-catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). beta-Catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All beta-catenin-positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with beta-catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of beta-catenin in c-myc/TGF-alpha HCCs. beta-Catenin activation confers additional growth and invasive advantages in a model of liver cancer already accelerated by synergistic activity of the c-myc and TGF-alpha transgenes.
Calvisi
Diego F
DF
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4262, USA.
Ladu
Sara
S
Factor
Valentina M
VM
Thorgeirsson
Snorri S
SS
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D010634:Phenobarbital / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D051176:beta Catenin; D010634:Phenobarbital