transforming-growth-factor-alpha and Hepatitis--Animal

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-alpha, 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-alpha 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.

Topics: Animals; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Epidermal Growth Factor; Helicobacter Infections; Hepatitis, Animal; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred A; Neoplasm Proteins; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Retinoblastoma Protein; Transforming Growth Factor alpha