Lack ofp53accelerates hepatocarcinogenesis in transgenic mice constitutively overexpressing c‐mycin the liver

Abstract

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.

Developmental Context Determines Latency of MYC-Induced Tumorigenesis

“…We found by PCR that tumors did not generally inactivate the second allele through deletion (Figure 10E). Our results extend previous findings that suggest that the lack of p53 function cooperates with MYC to induce HCC (Klocke et al 2001). We conclude that even a slight reduction of p53 function greatly facilitates the ability of MYC to induce tumorigenesis in adult hepatocytes.…”

Deleted in Liver Cancer 2 (DLC2) Was Dispensable for Development and Its Deficiency Did Not Aggravate Hepatocarcinogenesis

“…Since DLC1-deficient mice dies at embryonic stage, it would be interesting to see if hepatocyte-specific deficiency of DLC1 may predispose such mice to the development of HCC and to delineate the role of DLC2 deficiency in the development of HCC in these mice. It was demonstrated that loss of p53 would accelerate hepatocarcinogenesis in transgenic mice overexpressing c-myc [29]. It would be informative to cross DLC2-deficient mice with other knockout mice of tumor suppressor genes, such as p53 and/or transgenic mice overexpressing oncogenes such as c-myc and TGF-alpha [30].…”

c-MYC—Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease

“…Not surprisingly, lack of the molecular gatekeeper p53 accelerates HCC in c-MYC tg in the liver [28]. Enhanced tumor growth, pronounced malignant structure and an invasive growth pattern correlated with p53-deficiency in livers of alb-Cre + /c-MYC tg .…”