PMID- 22344786 OWN - NLM STAT- MEDLINE DCOM- 20130820 LR - 20161125 IS - 1098-2744 (Electronic) IS - 0899-1987 (Linking) VI - 52 IP - 7 DP - 2013 Jul TI - Higher susceptibility of spontaneous and NNK-induced lung neoplasms in connexin 43 deficient CD1 x AJ F1 mice: paradoxical expression of connexin 43 during lung carcinogenesis. PG - 497-506 LID - 10.1002/mc.21884 [doi] AB - 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(+/-) ) CD1 x AJ 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 (beta-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 CD1 x AJ 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. beta-catenin was weakly expressed in lung parenchyma. Though hyperplasias presented some cells with nuclear beta-catenin, NNK-induced tumors contained a higher number of this staining pattern. Also, no difference in beta-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. CI - Copyright (c) 2012 Wiley Periodicals, Inc. FAU - Fukumasu, Heidge AU - Fukumasu H AD - Laboratory of Experimental and Comparative Oncology, Department of Pathology, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Sao Paulo, Brazil. FAU - Avanzo, Jose L AU - Avanzo JL FAU - Sanches, Daniel S AU - Sanches DS FAU - Mennecier, Gregory AU - Mennecier G FAU - Mori, Claudia M C AU - Mori CM FAU - Dagli, Maria L Z AU - Dagli ML LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120217 PL - United States TA - Mol Carcinog JT - Molecular carcinogenesis JID - 8811105 RN - 0 (Carcinogens) RN - 0 (Connexin 43) RN - 0 (GJA1 protein, mouse) RN - 0 (Nitrosamines) RN - 0 (RNA, Messenger) RN - 0 (beta Catenin) RN - 7S395EDO61 (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone) SB - IM MH - Animals MH - Blotting, Western MH - Carcinogens/*toxicity MH - Cell Transformation, Neoplastic/*pathology MH - Connexin 43/*physiology MH - Disease Susceptibility MH - Female MH - Immunoenzyme Techniques MH - Lung Neoplasms/*etiology/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nitrosamines/*toxicity MH - RNA, Messenger/genetics MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - beta Catenin/genetics/*metabolism EDAT- 2012/02/22 06:00 MHDA- 2013/08/21 06:00 CRDT- 2012/02/21 06:00 PHST- 2011/09/20 00:00 [received] PHST- 2012/01/09 00:00 [revised] PHST- 2012/01/17 00:00 [accepted] PHST- 2012/02/21 06:00 [entrez] PHST- 2012/02/22 06:00 [pubmed] PHST- 2013/08/21 06:00 [medline] AID - 10.1002/mc.21884 [doi] PST - ppublish SO - Mol Carcinog. 2013 Jul;52(7):497-506. doi: 10.1002/mc.21884. Epub 2012 Feb 17.