HIGH-INCIDENCE OF SPONTANEOUS AND CHEMICALLY-INDUCED LIVER-TUMORS IN MICE DEFICIENT FOR CONNEXIN32

Connexins are subunits of gap junction channels, which mediate the dir ect 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 pro liferation [1,2], It has also been suggested that the loss of intercel lular communication via gap junctions may contribute to multistage car cinogenesis [3-5]. We have previously shown that transgenic mice that lack connexin32 (Cx32), the major gap junction protein expressed in he patocytes, express lower levels of a second hepatic gap junction prote in, Cx26, suggesting that Cx32 has a stabilizing effect on Cx26 [6], H ere, we report that male and female one-year-old mice deficient for Cx 32 had 25-fold more and 8-fold more spontaneous liver tumors than wild type mice, respectively, Incorporation of bromodeoxyuridine (BrdU) in to the liver was higher for Cx32-deficient mice than for wild-type mic e, suggesting that their hepatocyte proliferation rate was higher, Fur thermore, intraperitoneal injection, two weeks after birth, of the car cinogen diethylnitrosamine (DEN) led, after one year, both to more liv er tumors in Cx32-deficient mice than in controls, and to accelerated tumor growth, Loss of Cx32 protein from hepatic gap junctions is there fore likely to cause enhanced clonal survival and expansion of mutated ('initiated') cells, which results in a higher susceptibility to hepa tic tumors, Our results demonstrate that functional gag junctions inhi bit the development of spontaneous and chemically induced tumors in mo use liver.