Hepatocellular carcinomas (HCC) are among the most common malignancies in the world with tumor incidence approaching 150 per 100,000 per year in areas such as China. Although the incidence of liver cancer is lower in the United States, 60 percent of the chemicals determined by the National Toxicology Program to be carcinogens give rise to liver tumors in rats and mice. Interestingly, a number of these agents appear to function through tumor promoting rather than initiating mechanisms. Consequently, to appropriately assess the high risk from xenobiotic agents, it is necessary to determine the molecular events by which liver tumor promoters enhance the formation of Hepatocellular carcinomas. The investigators have evidence that suggests liver tumor promotion by phenobarbital (PB) is a process of natural selection for cells resistant to the growth inhibitory environment produced by PB. The results also suggest that the selective increase in mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor and TGFbeta levels in normal hepatocytes is important in establishing the mito-inhibitory selective pressure required for PB to promote the formation of liver tumors. Both the activation of the growth inhibitor, TGFbeta, and the degradation of the mitogen, IGFII, depend upon their binding to the M6P/IGFII receptor. The M6P/IGFII receptor is imprinted in mice and potentially in a subset of humans. They have also recently found a 78 percent loss of heterozygosity (LOH) at the M6P/IGFII receptor gene locus in human HCCs. These findings strongly support the postulate that this receptor function as a tumor suppressor in liver carcinogenesis. Therefore, the overall objective of this grant application is to determine the role of the M6P/IGFII receptor and TGFbeta in liver carcinogenesis. Specifically, they have proposed to: 1) determine the transcriptional control elements responsible for the modulation of M6P/IGFII receptor gene expression; 2) determine whether reduced expression of the M6P/IGFII receptor in liver tumors results from altered gene methylation; 3) determine whether the extent of LOH at the M6P/IGFII receptor gene locus in human HCC is dependent upon the etiology and stage of tumor development; 4) identify mutations in the remaining allele in HCCs and LOH at the M6P/IGFII receptor locus; and 5) determine, using transgenic mice, whether susceptibility to liver tumor promotion and carcinogenesis is dependent upon the M6P/IGFII receptor. The results of these studies should provide a better understanding of the role of the M6P/IGFII receptor and TGFbeta in liver tumor promotion, and enable us to assess substances for human carcinogenic risk with greater accuracy.
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