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 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.
Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA. ramljak@mail.ncifcrf.gov
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Ramljak
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Jones
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Diwan
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Perantoni
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Hochadel
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Anderson
D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D006520:Hepatitis, Animal / Q000150:complications / Q000378:metabolism / Q000382:microbiology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D004815:Epidermal Growth Factor; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases