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Carcinogenesis Advance Access published online on May 27, 2004
Carcinogenesis, doi:10.1093/carcin/bgh193
© 2004 by Oxford University Press
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Received December 2, 2003
Revised May 6, 2004
Accepted May 16, 2004

CARCINOGENESIS

Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of Connexin 43

José Luis Avanzo 1, Marc Mesnil 2, Francisco Javier Hernandez-Blazquez 3, Ivone Isabel Mackowiak 1, Claudia Madalena Cabrera Mori 1, Tereza Cristina da Silva 1, Sílvia Catarina Salgado Oloris 1, Ana Paula Gárate 1, Silvia Maria Gomes Massironi 4, Hiroshi Yamasaki 5, Maria Lúcia Zaidan Dagli 1*

1 Laboratory of Experimental Oncology, Department of Pathology, Faculty of Veterinary Medicine and Zootechny - University of São Paulo - Brazil
2 Laboratory of Biomembranes and Cell Signalization, Department of Physiology, Poitiers University, Poitiers - France
3 Department of Surgery, Faculty of Veterinary Medicine and Zootechny - University of São Paulo, São Paulo, SP - Brazil
4 Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP - Brazil.
5 School of Science, Kwansei Gakuin University, Uegara, Nishinomiya - Japan

* To whom correspondence should be addressed. E-mail: mlzdagli{at}usp.br.


  Abstract

Gap junction intercellular communication (GJIC) capacity and connexin expression are reportedly decreased in human lung cancer. The mechanisms by which connexins, the gap junction proteins, act as tumor suppressors are unclear. In order to understand what is the involvement of connexins in tumorigenesis, we analyzed the effect of the heterologous deletion of a Gja1 (Cx43 gene) on the development of lung adenomas in mice. Heterozygous (Cx43+/-) and wild-type mice (Cx43+/+) were treated or not with single doses of urethane at 15 and 17 days after birth. Twenty-five weeks later, both the number and size of nodules were increased in the Cx43+/- mice as compared with the Cx43+/+ mice. Moreover, the lesions were histologically more aggressive in the heterozygous mice. However, no increase of spontaneous lesions was observed in the lungs of untreated Cx43+/- mice. Heterozygous mice effectively presented lower expression of Cx43 genes and decreased Cx43 amounts. In conclusion, our results indicate that the deletion of one allele of the Cx43 gene clearly favors the carcinogenic effect of urethane administration and results in a higher susceptibility to lung adenoma formation in mice.


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