Abstract
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.
Highlights
The proto-oncogene KRAS, coding a membraneassociated GTPase signaling protein that regulates proliferation, differentiation, and cell survival, is mutated in 30–50% of lung adenocarcinomas, the most common histological subtype of non–small cell lung cancer (NSCLC) [1,2,3]
The results show that the deletion of the COX-2 gene inhibits the development of lung adenocarcinoma in mice carrying mutant K-ras
Using a gene knockout strategy, we demonstrated that genetic ablation of the COX-2 gene protects against K-ras-induced lung neoplasia, by decreasing hyperplastic bronchial epithelium and atypical adenomatous hyperplasia in K-ras/COX-2−/− mice
Summary
The proto-oncogene KRAS, coding a membraneassociated GTPase signaling protein that regulates proliferation, differentiation, and cell survival, is mutated in 30–50% of lung adenocarcinomas, the most common histological subtype of non–small cell lung cancer (NSCLC) [1,2,3]. Studies suggest that KRAS mutations play significant roles in the initiation and progression of lung cancer and contribute to the poor prognosis of the disease. COX-2 is overexpressed at most stages www.impactjournals.com/oncotarget of lung tumor progression, including in hyperplastic bronchial epithelium, atypical adenomatous hyperplasia and metastatic lung cancer [5,6,7]. Hida et al found that COX-2 is expressed in one-third of atypical adenomatous hyperplasias and carcinomas in situ, which again suggests that COX-2 plays an important role throughout the progression of lung cancer, from pre-malignant lesion to metastatic phenotype [5]. KRAS mutations are found in >90% of spontaneous and chemically-induced lung tumors [10]. The role of COX-2 in lung tumorigenesis in mice carrying the KRAS oncogene remains unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
