Higher susceptibility of spontaneous and NNK-induced lung neoplasms in connexin 43 deficient CD1xAJ F1 mice: Paradoxical expression of connexin 43 during lung carcinogenesis

Autor(es)

Fukumasu, Heidge ^[1] ; Avanzo, Jose L. ^[1] ; Sanches, Daniel S. ^[1] ; Mennecier, Gregory ^[1] ; Mori, Claudia M. C. ^[1] ; Dagli, Maria L. Z. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Pathol, Lab Expt & Comparat Oncol, BR-05508900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Molecular Carcinogenesis; v. 52, n. 7, p. 497-506, JUL 2013.
• Citações Web of Science: 9

Resumo

Connexins (Cxs) are proteins that form the communicating gap junctions, and reportedly have a role in carcinogenesis. Here, we evaluated the importance of Connexin43 (Cx43) in spontaneous and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis. Male wild-type (Cx43+/+) and hemizygote (Cx43+/-) CD1xAJ F1 mice were injected with NNK or saline. After 60 weeks mice were euthanized; lung nodules were counted, measured, and fixed in formalin or snap frozen. Immunohistochemistry for Cx43 and Beta-catenin (-catenin) was performed and Cx43 mRNA expression was evaluated by real-time PCR. Cx43 deletion significantly increased the incidence and number of spontaneous nodules in the CD1xAJ F1 mice and the number of gross lesions and the aggressiveness of lesions in NNK-treated mice. Cx43 mRNA increased significantly and was correlated with the aggressiveness of tumors, although lesions from Cx43+/- mice expressed less Cx43 RNAm than their counterparts. Lung parenchyma presented a Cx43 immunostaining pattern with points or plaques between cells. In hyperplasias and adenomas, Cx43 was found in the membrane and in cytoplasm. Malignant lesions presented increased Cx43 in cytoplasm and a few membrane spots of immunostaining. -catenin was weakly expressed in lung parenchyma. Though hyperplasias presented some cells with nuclear -catenin, NNK-induced tumors contained a higher number of this staining pattern. Also, no difference in -catenin occurred between both genotypes independently of the histological grade. In summary, our results indicate that Cx43 acts as a tumor suppressor gene in early lung tumorigenesis and loses this property in advanced carcinogenesis. Therefore, Cxs are better classified as conditional tumor suppressors. (c) 2012 Wiley Periodicals, Inc. (AU)

• Processo FAPESP: 05/54194-4 - Avaliação da ação quimiopreventiva do guaraná (Paullinia cupana Mart. var. sorbilis) em camundongos com deficiência na expressão da Cx43 submetidos à carcinogênese pulmonar induzida por carcinógeno do tabaco, NNK
• Beneficiário: Heidge Fukumasu
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 04/07815-0 - Avaliação da ação quimiopreventiva do guaraná (Paullinia cupana Mart. var. sorbilis) em camundongos com deficiência na expressão da Cx43 submetidos a carcinogênese pulmonar induzida por carcinógeno do tabaco (4-(metilnitrosamino) -1 (3-piridil) -1- butanona)
• Beneficiário: Maria Lucia Zaidan Dagli
• Modalidade de apoio: Auxílio à Pesquisa - Regular