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Expression of the c-raf Protooncogene, -Glutamyltranspeptidase, and Gap Junction Protein in Rat Liver Neoplasms¹

McArdle Laboratory for Cancer Research, The Medical School, University of Wisconsin, Madison, Wisconsin 53706 [D. G. B., M. J. N., H. C. P.]; the Department of Anatomy and Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 [D. L. P.]; and the Laboratory of Viral Carcinogenesis, Frederick Cancer Research Facility, National Cancer Institute, Frederick, Maryland 21701 [U. R. R.]

Female Harlan Sprague-Dawley and F-344 rats were subjected to a 70% hepatectomy and 18 h later given one dose of 30 mg diethylnitrosamine/kg body weight. Beginning 1 week later, the animals were fed a diet containing 0.05% phenobarbital. Groups of rats were sacrificed 6 and 15 months later, and the livers were either frozen for cryostat sectioning or used to isolate RNA. Primary liver tumors present in these animals were used for RNA isolation, and a portion was taken for histopathological analysis. Eleven of 13 primary lesions, consisting of either neoplastic nodules or hepatocellular carcinomas, showed elevated levels of mRNA for the c-raf protooncogene. Increased c-raf mRNA in these tumors appeared to be unrelated to their cellular proliferative status inasmuch as the levels of c-raf mRNA did not correlate with levels of H4 histone mRNA. Decreased expression of the major rat liver gap junction protein mRNA was observed in all of the primary tumors. Immunocytochemical analysis using an anti-gap junction antibody revealed a decrease in gap junction immunoreactivity in some but not all preneoplastic focal lesions. All preneoplastic foci having positive -glutamyltranspeptidase enzyme staining also exhibited a marked increase in -glutamyltranspeptidase mRNA as determined by in situ hybridization. The possible relation of alternations of the mRNA levels of c-raf and the gap junction protein to the further development of preneoplastic foci is discussed.

¹ This work was supported by National Cancer Institute Grants CA-07652, CA-07175, and CA-22484.

² Present address: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical School, Kansas City, KS 66103.

³ To whom requests for reprints should be addressed.

Received 6/29/87. Revised 11/ 9/87. Accepted 12/11/87.

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