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Altered Expression of Retrovirus-like Sequences and Cellular Oncogenes in Mice Fed Methyl-deficient Diets¹

Comprehensive Cancer Center and Division of Environmental Sciences of the School of Public Health, Columbia University, New York, New York 10032 [L. L. H., S. H., I. B. W.], and The Lindsley F. Kimball Research Institute of the New York Blood Center, New York, New York 10021 [E. W., M. D.]

Methyl-deficient (lipotrope-deficient) diets enhance liver carcinogenesis in rodents. Although the mechanisms responsible for the cancerpromoting activity of such diets have not been identified, they have been observed to cause impaired immune response, alterations in methylation of liver RNA and DNA, and enhanced susceptibility to oxidative damage. Since alterations in gene expression may also play a critical role, the present studies examined the expression of the c-myc, c-H-ras, epidermal growth factor receptor, and ornithine decarboxylase genes, as well as endogenous retrovirus-like sequences, in C57BL/6J x C3H/HeJ F₁ mouse liver during the first 2 weeks of feeding of a methyl-deficient diet. The kinetics of liver cell proliferation was investigated in parallel. Increased [³H]thymidine incorporation into liver DNA was found at day 4 and reached a maximum at days 7–11 after commencement of the methyl-deficient diet, when compared to age-matched mice fed a complete diet. Northern blot analysis of polyadenylated liver RNA samples indicated an increase in the levels of RNA homologous to Moloney murine leukemia virus and intracisternal A particle sequences but no significant change in the level of VL30 retrovirus-related RNA in the samples from mice fed methyl-deficient diets. A marked increase in the levels of c-myc and a slight increase in the levels of ornithine decarboxylase and c-H-ras transcripts were seen in the liver RNA samples from the treated mice. Of particular interest was a decrease in the abundance of epidermal growth factor receptor transcripts in the liver RNA samples from the treated mice. These changes in cellular levels of specific RNA resemble, in several respects, those we have previously described in rodent liver during regeneration and tumor promotion and also those seen in rodent hepatomas. They may reflect, therefore, a common profile of gene expression relevant to cell proliferation.

¹ This study was supported by National Cancer Institute Grants CA021111 (to I. B. W.), and CA47600 (to E. W.), the National Foundation for Cancer Research (to I. B. W.), and the American Institute of Cancer Research (to E. W. and to I. B. W.).

² To whom requests for reprints should be addressed.

Received 12/ 6/88. Revised 3/27/89. Accepted 4/18/89.

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