Modulation of liver tumorigenesis in Connexin32-deficient mouse.
Connexin32 (Cx32) is the major gap junction forming protein in liver. Mice deficient in Cx32 demonstrate enhanced liver tumor formation, but are resistant to promotion of hepatocarcinogenesis by the model tumor promoter phenobarbital (PB). Here, we re-evaluate data on the number and sizes of glucose-6-phosphatase (G6Pase)-deficient liver lesions, both in Cx32-wildtype (WT) and Cx32-null male mice, obtained from two earlier experiments with similar protocols but paradoxical outcomes. In these experiments, enzyme-altered lesions were induced in mice of both strains by a single injection of N-nitrosodiethylamine (DEN) at age 6 weeks with a dose of 90 microg/g body weight (experiment 1) or at age 2 weeks with 10 microg/g body weight (experiment 2). Three weeks after DEN treatment groups of mice (sub-divided by Cx32 status) were also started on a PB-containing (0.05%) diet to test the responsiveness of the lesions to the tumor promoter. Additionally, for experiment 1, tumors were analyzed for the presence of Ha-ras and beta-catenin mutations. Based on the mutational analysis and the mathematical analysis of the G6Pase-deficient lesions, the two studies are consistent with the hypothesis of two types of lesions, 'late-type' lesions which are mainly characterized by beta-catenin mutations, and 'early-type' lesions that are frequently (but not exclusively) Ha-ras mutated. This concept affords an explanation as to the differential response seen in the two experiments with regard to Cx32 status and the role of PB as a tumor promoter (experiment 1) or inhibitor (as in experiment 2). Our findings also underscore the importance of the timing (6 weeks versus 2 weeks) of the genotoxic insult in relation to the developmental stage of the liver and the importance of clonal selection during tumor promotion.
Luebeck
E Georg
EG
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA. gluebeck@fhcrc.org
Buchmann
Albrecht
A
Schneider
Daniela
D
Moolgavkar
Suresh H
SH
Schwarz
Michael
M
D000367:Age Factors; D000818:Animals; D017630:Connexins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D016013:Likelihood Functions; D008113:Liver Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D005952:Glucose-6-Phosphatase; D000097002:Gap Junction beta-1 Protein