Bcl-2 expression inhibits liver carcinogenesis and delays the development of proliferating foci.
Tumor development is thought to require both increased proliferation and inhibition of apoptosis. However, the relationship between cell replication and cell death in liver tumorigenesis is complex because both proliferation and apoptosis increase during hepatocarcinogenesis. To investigate the effect of the anti-apoptotic gene Bcl-2 in liver carcinogenesis, we established a line of double transgenic mice that express transforming growth factor-alpha (TGF-alpha), a liver mitogen, and Bcl-2. Double transgenic mice, TGF-alpha and Bcl-2 single transgenics, and wild type received an injection of diethylnitrosamine at 15 days of age. This alkylating agent induces liver carcinogenesis and its effect is greatly enhanced by TGF-alpha. We report that Bcl-2 expression inhibited diethylnitrosamine-induced liver carcinogenesis and counteracted the enhancing effect of TGF-alpha. Bcl-2 delayed the growth of proliferative foci at the early stages of carcinogenesis and inhibited cell proliferation in these foci. The effect of Bcl-2 on liver carcinogenesis is consistent with its reported ability to interfere with cell replication. The data demonstrate that the expression of an anti-apoptotic gene during liver carcinogenesis causes a delay rather than an increase in tumorigenesis.
Pierce
Robert H
RH
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Vail
Mary E
ME
Ralph
Leah
L
Campbell
Jean S
JS
Fausto
Nelson
N
D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000502:physiology; D004052:Diethylnitrosamine / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D005838:Genotype; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000502:physiology
D000477:Alkylating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016211:Transforming Growth Factor alpha; D004052:Diethylnitrosamine