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Lack of p53 accelerates hepatocarcinogenesis in transgenic mice constitutively overexpressing c-myc in the liver

: Klocke, R.; Bartels, T.; Jennings, G.; Brand, K.; Halter, R.; Strauss, M.; Paul, D.

FASEB journal 15 (2001), No.8, pp.1404-1406
ISSN: 0892-6638
Journal Article
Fraunhofer ITA ( ITEM) ()
animal; carcinoma; hepatocellular; neoplastic cell transformation; Genetic Predisposition to Disease; liver; liver neoplasm; transgenic mouse; biological model; protein p53; Proto-Oncogene Proteins c-myc; survival analysis

The role of the tumor suppressor function of p53 in the process of hepatocellular carcinoma (HCC) development is still enigmatic in view of uncertainties with respect to the phenotype of most p53 mutations found in human HCCs. We therefore analyzed the effect of the p53 knockout (p53KO) genotype, which imparts a clear-cut loss of function, on hepatocarcinogenesis in livers of transgenic mice prone to develop this tumor type. Deterministic HCC formation in mice overexpressing transgenes encoding murine c-myc, or c-myc plus the secretable human epidermal growth factor (EGF) analogue IgEGF, in the liver was accelerated in the p53KO background as indicated by enhanced relative liver weights and reduced survival times of mice. In contrast, HCC formation was not affected by lack of p53 in IgEGF transgenics. Because p53KO mice are not HCC prone, lack of p53 contributed to hepatocarcinogenesis during progression provided that c-myc was overexpressed in the liver. Thus, deterministic HCC development occurs not simply because of the accumulation of genetic changes in individual hepatocytes; the order in which these changes occur also determines the propensity for liver neoplasia. Enhanced proliferation of hepatocytes was accompanied by markedly reduced p21. levels in tumorous livers of c-myc/IgEGF/p53KO mice. Concomitantly with unaltered p53-independent apoptotic activities, it caused enhanced hyperplasia and accelerated HCC development in livers enlarged fivefold, which killed the mice at 1.9 months of age.