The FASEB Journal, Vol 11, 60-67, Copyright © 1997 by The Federation of American Societies for Experimental Biology

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Imprinted genes in liver carcinogenesis

AT De Souza, T Yamada, JJ Mills and RL Jirtle
Department of Safety of Medicines, Zeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.

Each cell contains both maternal and paternal copies of all genes except those that reside on the sex chromosomes. However, because of a phenomenon termed genomic imprinting, not all genes are biallelically expressed. Imprinted genes play an important role in embryogenesis and recently have also been shown to be mechanistically involved in carcinogenesis. The growing list of imprinted genes implicated in tumor formation includes both a growth factor gene, insulin-like growth factor 2 (IGF2), and a receptor gene, mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R). Elevated expression of IGF2 is often found in tumors, and loss of imprinting is one mechanism by which its expression is deregulated. The M6P/IGF2R functions in the inactivation of the mitogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta. Recently, a high frequency of loss of heterozygosity with concomitant mutations in the remaining allele has been shown to occur at the M6P/IGF2R locus (i.e., 6q26-q27) in both human liver and breast tumors, suggesting that this gene functions as a tumor suppressor. Expression of the M6P/IGF2R gene is biallelic in most humans but is monoallelic in mice. This species difference in M6P/IGF2R gene imprinting provides one plausible explanation for the enhanced sensitivity of mice to tumor formation. Furthermore, these findings suggest that species differences in the imprinted status of genes mechanistically involved in tumor formation should be factored into human carcinogenesis risk assessment models when extrapolating results from mice to humans.

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