Deletion of cyclooxygenase-2 inhibits K-ras–induced lung carcinogenesis
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Yong Pan1, Yan Jiang1, Lin Tan1, Murali K. Ravoori2, Mihai Gagea3, Vikas Kundra2,4, Susan M. Fischer5, Peiying Yang1
1Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Peiying Yang, e-mail: email@example.com
Keywords: COX-2, K-ras oncogene, lung adenocarcinoma, mouse, MAP kinase
Received: August 04, 2015 Accepted: September 21, 2015 Published: October 03, 2015
The purpose of this study was to identify the role COX-2 plays in K-ras–induced lung carcinogenesis. We crossed COX-2–homozygous knockout mice with K-rasLA1 (G12D) expressing mice to obtain COX-2–deficient mice with K-ras expression (K-ras/COX-2−/− mice) and COX-2 wild type mice with K-ras expression (K-ras mice). At 3.5 months of age, the K-ras/COX-2−/− mice had significantly fewer lung adenocarcinomas and substantially smaller tumors than K-ras mice. K-ras/COX-2−/− mice also had significantly fewer bronchioalveolar hyperplasias than K-ras mice. Compared with lung tumors from K-Ras mice, the levels of prostaglandin E2 (PGE2) were significantly lower, whereas levels of the PGE2 metabolite 13,14-dihydro-15-keto-PGE2 were significantly higher, in lung tumors from K-ras/COX-2−/− mice. In addition, K-ras/COX-2−/− mice had strikingly lower rates of tumor cell proliferation and expressed less MEK and p-Erk1/2 protein than K-ras mice did. In line with this, knocking down COX-2 in mutant K-ras non-small cell lung cancer A549 cells reduced colony formation, PGE2 synthesis and ERK phosphorylation compared to that of vector control cells. Taken together, these findings suggest that COX-2 deletion contributes to the repression of K-ras–induced lung tumorigenesis by reducing tumor cell proliferation, decreasing the production of PGE2, and increasing the production of 13,14-dihydro-15-keto-PGE2, possibly via the MAPK pathway. Thus, COX-2 is likely important in lung tumorigenesis, and COX-2 and its product, PGE2, are potential targets for lung cancer prevention.
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