Abstract
Connexins are a family of transmembrane proteins essential for the gap junctions, which mediate cell-to-cell communication. Several connexins are reported to be tumor suppressors, and we have established transgenic (Tg) rats with a connexin 32 (Cx32) dominant negative mutant showing high sensitivity to early-stage diethylnitrosamine (DEN)-induced liver carcinogenesis. In this study, we carried out two independent experiments using Tg rats to further investigate the roles of disrupted Cx32 in late-stage carcinogenesis (carcinoma induction and metastasis) in the liver. In the first experiment, of 50 weeks’ duration, DEN was administered at 6 weeks of age and at 26 weeks to explore the effects of carcinogen treatments at different stages. The number of hepatocellular carcinomas (HCCs) was significantly increased in Tg compared with non-Tg rats. The second experiment focused on the effects of Cx32 disruption on metastasis by HCCs induced by administration of DEN and N-nitrosomorpholine. Only Tg rats had multiple metastases of HCCs in the lung, and the development and growth of HCCs was dramatically accelerated in Tg compared to non-Tg rats. Thus, normal function of Cx32 may be essential for suppression of both early and late stages of hepatocarcinogenesis.
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Acknowledgment
We thank Dr. Malcolm A. Moore for his kind linguistic advice during preparation of the manuscript. This study was supported in part by a grant-in-aid from the Japan Health Sciences Foundation, Research on Health Sciences Focusing on Drug Innovation; a grant-in-aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control; and a grant-in-aid for cancer research from the Ministry of Health, Labor and Welfare of Japan, as well as by the Society for Promotion of Pathology (Nagoya, Japan).
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Hokaiwado, N., Asamoto, M., Futakuchi, M. et al. Both Early and Late Stages of Hepatocarcinogenesis Are Enhanced in Cx32 Dominant Negative Mutant Transgenic Rats with Disrupted Gap Junctional Intercellular Communication. J Membrane Biol 218, 101–106 (2007). https://doi.org/10.1007/s00232-007-9053-9
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DOI: https://doi.org/10.1007/s00232-007-9053-9