Carcinogenesis Advance Access originally published online on January 23, 2004
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Carcinogenesis, Vol. 25, No. 6, 901-908,
June 2004
Carcinogenesis vol.25 no.6 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Activation of ß-catenin provides proliferative and invasive advantages in c-myc/TGF-
hepatocarcinogenesis promoted by phenobarbital
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4262, USA
1 To whom correspondence should be addressed Email: snorri_thorgeirsson{at}nih.gov
Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/transforming growth factor (TGF)-
transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring ß-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/ß-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 ß-catenin mutations in c-myc/TGF--driven tumors. The frequency of ß-catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF- mice treated with PB (15/28; 53.6%) as compared with that in control HCCs (2/28; 7.1%). Furthermore, an intact ß-catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF- untreated mice displayed loss of heterozygosity at the ß-catenin locus. Strikingly, in the majority of PB-treated HCCs ß-catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). ß-Catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All ß-catenin-positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with ß-catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of ß-catenin in c-myc/TGF- HCCs. ß-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- transgenes.
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