Cell proliferation and growth is believed to be necessary for promotion of tumors and carcinogenesis. In the case of liver, hepatocyte replication and growth is an essential process during the long period of progression to cancer. Recently, a potent hepatomitogen (Hepatocyte Growth Factor, HGF) has emerged as one of the most likely hepatotrophic agents responsible for maintenance of hepatocyte growth and proliferation. Despite significant progress in characterizing the biochemical and biological properties of HGF, the precise physiological role of this potent epithelial mitogen is unknown in normal and abnormal cell growth. We have generated several lines of transgenic mice harboring a human HGF cDNA under the transcriptional control of mouse Metallothionein 1 promoter. These transgenic animals can provide a suitable model system to further explore the effects of directed high expression of HGF in liver tumor promotion and carcinogenesis induced by different xenobiotics. Utilizing these animals we would like to address the following questions: A) What are the effects of long term and continuous expression of HGF in MT1-HGF transgenic mice in the liver and other tissues? B) Does the chronic overexpression of HGF in MT1-HGF transgenic mice in conjunction with different liver tumor promoters and carcinogens lead to enhanced appearance of pre-neoplastic and neoplastic lesions in the liver of MT1-HGF transgenic mice? C) What are the molecular signals involved in the induction of HGF gene expression in regenerating or xenobiotic treated liver in normal or the MT1-HGF transgenic animals? Answers to these questions may provide further insight to the molecular mechanisms by which tumor promoters and growth factors induce chronic cell proliferation and cancer. Employing techniques and specific molecular probes for HGF detection which are well-established in our laboratory we will analyze the expression of HGF and its receptor (the product of proto-oncogene cMET) in the MT1-HGF transgenic mice treated with or without liver tumor promoters phenobarbital, ciprofibrate, and the carcinogen Diethylnitrosamine to determine whether there is any correlation between the high HGF expression and histopathological abnormalities such as hyperplasia and neoplasia in these animals. The expression of oncogenes c-myc, c-fos, and c-jun which are believed to mediate the mitogenic response of several polypeptide growth factors and also known to be transiently overexpressed during liver regeneration and in some liver tumors (especially c-myc) will be investigated in MT1-HGF transgenic and control mice treated with or without liver tumor promoters. We will also attempt to establish hepatocyte cell lines derived from the neoplastic and normal livers of HGF-transgenic mice which may be suitable for in vitro mutagenesis assays.
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