Journal Article

Activation of β-catenin provides proliferative and invasive advantages in <i>c-myc</i>/TGF-α hepatocarcinogenesis promoted by phenobarbital

Diego F. Calvisi, Sara Ladu, Valentina M. Factor and Snorri S. Thorgeirsson

in Carcinogenesis

Volume 25, issue 6, pages 901-908
Published in print June 2004 | ISSN: 0143-3334
Published online June 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh083
Activation of β-catenin provides proliferative and invasive advantages in c-myc/TGF-α hepatocarcinogenesis promoted by phenobarbital

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Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/transforming growth factor (TGF)-α transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring β-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/β-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 β-catenin mutations in c-myc/TGF-α-driven tumors. The frequency of β-catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF-α mice treated with PB (15/28; 53.6%) as compared with that in control HCCs (2/28; 7.1%). Furthermore, an intact β-catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF-α untreated mice displayed loss of heterozygosity at the β-catenin locus. Strikingly, in the majority of PB-treated HCCs β-catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). β-Catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All β-catenin-positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with β-catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of β-catenin in c-myc/TGF-α HCCs. β-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-α transgenes.

Keywords: APC, adenomatous polyposis coli; DEN, diethylnitrosamine; HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; MMP, matrix metalloproteinase; MUC1, mucin 1; NAinv, nuclear accumulation in the tumor invasion front; PB, phenobarbital; PCNA, proliferating cell nuclear antigen; TGF, transforming growth factor

Journal Article.  4835 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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