Overview of the Molecular Biology of Hepatocellular Neoplasms and Hepatoblastomas of the Mouse Liver

Abstract

The molecular pathogenesis of chemically induced hepatocellular neoplasms and hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the β-catenin/Wnt signaling pathway as was recently described for human liver neoplasms. The objectives of this research were to characterize the mutation frequency and spectrum of β-catenin mutations and the intracellular localization of β-catenin protein accumulation in chemically induced hepatoblastomas and hepatocellular neoplasms. In the majority of the hepatoblastomas examined by immunohistochemical methods, both nuclear and cytoplasmic localization of β-catenin protein were detected, whereas in hepatocellular adenomas and carcinomas and normal liver only membrane staining was observed. Genomic DNA was isolated from paraffin sections of each liver tumor. β-catenin exon 2 (corresponds to exon 3 in humans) genetic alterations were identified in the majority of hepatoblastomas from exposed mice. Deletion mutations were identified more frequently than point mutations in hepatoblastomas. Hepatocellular adenomas and carcinomas from treated mice had mutations in exon 2 of the β-catenin gene which ranged from 32–43%, while 10% β-catenin mutations were detected in spontaneous neoplasms. By immunohistochemical methods cyclin D1 was observed in most nuclei of hepatoblastomas and strong expression of cyclin D1 was confirmed by Western analysis regardless of treatment. The cumulative data suggests that β-catenin mutations with upregulation of the β-catenin protein and Wnt signaling most likely increased cyclin D1 expression. Cyclin D1 may provide an advantage during tumor progression of hepatocellular neoplasms and hepatoblastomas. The review will also focus on other genes which are important in mouse and human liver tumors.