Details

Autor(en) / Beteiligte

• Tward, Aaron Daniel

Titel

The proto-oncogene MET in liver differentiation and liver cancer

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2005

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The proto-oncogene MET encodes a receptor tyrosine kinase Met with diverse roles in development and cancer. I have utilized mouse models and samples from human tumors to explore the role of MET in liver differentiation and liver cancer. Overexpression of human MET in the liver during embryogenesis and continuously thereafter induced the sustained proliferation of hepatocyte progenitor cells and prevented their differentiation into mature hepatocytes. Inactivation of the overexpressed MET then permitted the progenitor cells to exit the cell cycle, differentiate into mature hepatocytes, and form a normal liver. Overexpression of MET in adult mice induced dysplasia that preceded hepatocellular carcinoma. In transgenic lines that expressed MET at relatively lower levels in the liver, mice first developed hyperplastic and dysplastic lesions and later hepatocellular carcinomas and adenomas. Activation of the Met kinase coincided with the onset of hyperplasia, and continued to be present in dysplastic foci, hepatocellular carcinomas, and hepatocellular adenomas. The transition to hepatocellular carcinoma coincided with activating mutations of the gene encoding β-catenin. The transition to hepatocellular adenoma coincided with loss of phenylalanine hydroxylase, a target gene of hepatocyte nuclear factor 1α (HNF1α). I confirmed the pathogenic roles of activation of Met and β-catenin or loss of HNF1α by hydrodynamically transfecting alleles of each of these into the liver of wild type mice. Activation of Met and β-catenin in combination induced multifocal hepatocellular carcinoma, whereas activation of Met and inactivation of HNF1α in combination induced multifocal hepatocellular adenoma. In a subset of human hepatocellular carcinomas, activation of the Met kinase strongly correlated with activating mutations in the gene encoding β-catenin. This work suggests approaches for the expansion of hepatic progenitor cells for therapeutic use and for the treatment of human hepatocellular carcinoma, and provides mouse models for the pre-clinical testing of those therapeutics.