High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32.
Connexins are subunits of gap junction channels, which mediate the direct transfer of ions, second messenger molecules and other metabolites between contacting cells. Gap junctions are thought to be involved in tissue homeostasis, embryonic development and the control of cell proliferation [1,2]. It has also been suggested that the loss of intercellular communication via gap junctions may contribute to multistage carcinogenesis [3-5]. We have previously shown that transgenic mice that lack connexin32 (Cx32), the major gap junction protein expressed in hepatocytes, express lower levels of a second hepatic gap junction protein, Cx26, suggesting that Cx32 has a stabilizing effect on Cx26 [6]. Here, we report that male and female one-year-old mice deficient for Cx32 had 25-fold more and 8-fold more spontaneous liver tumors than wild-type mice, respectively. Incorporation of bromodeoxyuridine (BrdU) into the liver was higher for Cx32-deficient mice than for wild-type mice, suggesting that their hepatocyte proliferation rate was higher. Furthermore, intraperitoneal injection, two weeks after birth, of the carcinogen diethylnitrosamine (DEN) led, after one year, both to more liver tumors in Cx32-deficient mice than in controls, and to accelerated tumor growth. Loss of Cx32 protein from hepatic gap junctions is therefore likely to cause enhanced clonal survival and expansion of mutated ('initiated') cells, which results in a higher susceptibility to hepatic tumors. Our results demonstrate that functional gap junctions inhibit the development of spontaneous and chemically induced tumors in mouse liver.
Temme
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A
Institut für Genetik, Abt. Molekulargenetik, Universität Bonn, Römerstr. 164, 53117 Bonn, Germany.
Buchmann
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A
Gabriel
H D
HD
Nelles
E
E
Schwarz
M
M
Willecke
K
K
D000818:Animals; D015152:Blotting, Northern; D001973:Bromodeoxyuridine / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D017630:Connexins / Q000172:deficiency / Q000502:physiology*; D004052:Diethylnitrosamine / Q000494:pharmacology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015994:Incidence; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000097002:Gap Junction beta-1 Protein
D001973:Bromodeoxyuridine; D002273:Carcinogens; D017630:Connexins; D004052:Diethylnitrosamine; D000097002:Gap Junction beta-1 Protein