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Carcinogenesis |
Institut für Toxikologie, 72074 Tübingen [O. M., A. B., J. W., M. S.], and Institut für Genetik, 53117 Bonn [A. R., T. O., K. W.], Germany
Connexin32 (Cx32) is the major gap junction forming protein in liver. We
have recently shown that hepatocarcinogenesis is strongly enhanced in
mice deficient in Cx32, demonstrating that lack of functional Cx32
accelerates liver tumorigenesis. Many tumor-promoting agents, including
phenobarbital, block gap junctional intercellular communication
in vitro, and it has been suggested that this effect is
relevant for clonal expansion of neoplastic cells in
vivo. We have now tested this hypothesis by analyzing the
potency of phenobarbital as a liver tumor promoter in male
Cx32-wild-type (Cx32Y/+) and Cx32-null
(Cx32Y/-) mice. Preneoplastic and neoplastic liver lesions
were induced in 6-week-old male mice by a single injection of 90 µg/g
body weight of N-nitrosodiethylamine, and groups of mice
were subsequently kept on phenobarbital-containing (0.05%) or control
diet for 39 weeks. Frozen liver sections were prepared, and
(pre)neoplastic lesions were identified by their deficiency in
glucose-6-phosphatase staining. In addition, the number and size of
macroscopically visible tumors were monitored. Phenobarbital led to a
5-fold increase in the volume fraction occupied by
glucose-6-phosphatase-deficient liver lesions in Cx32Y/+
mice, whereas there was no such increase in Cx32Y/- mice.
Even more pronounced differences were observed with respect to tumor
response. Whereas phenobarbital clearly promoted the occurrence of
numerous large hepatomas in Cx32Y/+ mice, no such effect
was seen in Cx32Y/- mice. These results demonstrate, for
the first time, that functional Cx32 protein is required for tumor
promotion by phenobarbital.
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