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Epidermal Growth Factor and Transforming Growth Factor--associated Overexpression of Cyclin D1, Cdk4, and c-Myc during Hepatocarcinogenesis in Helicobacter hepaticus-infected A/JCr Mice¹

Laboratory of Comparative Carcinogenesis [D. R., A. B. J., A. O. P., L. M. A.] and Intramural Research Support Program, SAIC Frederick [B. A. D., J. F. H.], National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Helicobacter hepaticus is a new bacterial species that is homologous to Helicobacter pylori, a human gastric carcinogen. H. hepaticus causes chronic active hepatitis, with progression to hepatocellular tumors. We hypothesized that chronic up-regulation of epidermal growth factor (EGF), transforming growth factor-, and nuclear oncogenes (cyclin D1 and c-Myc), all known to transform by overexpression, might contribute to tumorigenesis. Livers from mice that were 6–18 months old were analyzed, including nonneoplastic and preneoplastic tissues and tumors, along with age-matched controls, by immunohistochemistry and immunoblotting. EGF and transforming growth factor- were increased at the earliest stage, with a further increase in EGF in tumors. Cyclin D1, cyclin-dependent kinase 4, and c-Myc were strongly increased in all infected livers, with even greater increases in tumors. An increase in cyclin D1/cyclin-dependent kinase 4 complex was also demonstrated in tumors, and its functionality was confirmed by an increase in the hyperphosphorylated:hypophosphorylated retinoblastoma protein ratio. Our findings suggest a possible cooperation of growth factors, cell cycle proteins, and transcription factors during the development of H. hepaticus-associated liver tumors and may have relevance to human cancers associated with bacterial, viral, or parasitic infections.

¹ The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

² To whom requests for reprints should be addressed, at Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick Cancer Research and Development Center, Building 538, Room 206, Frederick, MD 21702-1201. Phone: (301) 846-1246; Fax: (301) 846-5946; E-mail: ramljak@mail.ncifcrf.gov.

Received 2/11/98. Accepted 6/17/98.

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