EPIDERMAL GROWTH-FACTOR AND TRANSFORMING GROWTH FACTOR-ALPHA-ASSOCIATED OVEREXPRESSION OF CYCLIN D1, CDK4, AND C-MYC DURING HEPATOCARCINOGENESIS IN HELICOBACTER HEPATICUS-INFECTED A JCR MICE/

Helicobacter hepaticus is a new bacterial species that is homologous t o 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-alpha, and nuclear oncogenes (cyclin D1 and c-Myc), all known to transform by overexpression, might contri bute to tumorigenesis. Livers from mice that were 6-18 months old mere analyzed, including nonneoplastic and preneoplastic tissues and turne rs, along with age-matched controls, by immunohistochemistry and immun oblotting. EGF and transforming growth factor-cr mere 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 in fected livers, with even greater increases in tumors. An increase in c yclin D1/cyclin-dependent kinase 4 complex was also demonstrated in tu mors, and its functionality mas confirmed by an increase in the hyperp hosphorylated:hypophosphorylated retinoblastoma protein ratio. Our fin dings suggest a possible cooperation of growth factors, cell cycle pro teins, and transcription factors during the development of H. hepaticu s-associated liver tumors and may have relevance to human cancers asso ciated with bacterial, viral, or parasitic infections.