Abstract 895: Genetic deletion of cyclooxygenase-2 suppresses K-ras induced lung tumorigenesis

Abstract

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Proto-oncogene K-ras is mutated in 30-50% of lung adenocarcinomas, the most common histological subtype of the non-small cell lung cancer. Cyclooxygenases are the key enzymes in the conversion of arachidonic acid to prostaglandins (PGs) which are thought to promote tumor growth, angiogenesis and metastasis in various tumors including lung cancer. However, the role of cyclooxygenase 2 (COX-2) in lung tumorigenesis in mice carrying the K-ras oncogene remains unclear. We evaluated the contribution of COX-2 in lung tumorigenesis in K-rasLA1(G12D) mice and its relevant molecular mechanisms. We used a genetic knockout approach by crossing COX-2 homozygous mice (COX-2-/-) with a mouse strain which develops lung tumorigenesis driven by mutant K-ras (K-rasLA1) to obtain COX-2 deficient mice with K-ras expression (K-ras/COX-2-/-) and COX-2 wild type mice with K-ras expression (K-ras). Loss of COX-2 was associated with a significant reduction in both multiplicity and tumor volume of lung adenocarcinoma examined by ex-vivo MRI. The average number of lung nodules in K-ras/COX-2-/- mice was 6.8 per mouse which was significantly less than that of K-ras mice (19.8) (p<0.05). Similarly, tumor size in K-ras mice (65.6 ± 31.1 mm3) was larger than that of K-ras/COX-2-/- mice (25.5 ± 8.7 mm3). Histological examination of mouse lung demonstrated that there was a significantly higher incidence of bronchioalveolar hyperplasia in lung tissues of the K-ras group (9.5±3.2) than in the K-ras/COX-2-/- group (5.3±2.5) (p<0.05). In line with this, studying tumor cell proliferation by Ki67 staining suggested that COX-2 deletion in K-ras mice was associated with less lung tumor cell proliferative potential evidenced by Ki67 positive cells being significantly decreased from 6.2% in K-ras mice to 2.9% in K-ras/COX-2-/- mice. The level of PGE2 was notably lower in lung tumor tissue derived from K-ras/COX-2-/- mice than that of K-ras mice. Similarly, the urinary metabolite of PGE2, PGEM, was also significantly reduced by 3-fold in K-ras/COX-2-/- mice in comparison with K-ras mice. In contrast, level of 13,14-dihydro-15-keto-PGE2, a metabolite of PGE2 in K-ras/COX-2-/- mouse lung tumor tissue was significantly increased by almost 3-fold. Furthermore, MEK and p-ErK1/2 expressions significantly decreased in lung tissues of K-ras/COX-2-/- mice compare to that of K-ras mice. Together, our data suggest that COX-2 deletion contributes to repression of K-ras-induced lung tumorigenesis through reducing tumor cell proliferation rate, decreasing production of PGE2, and increasing 13,14-dihydro-15-keto-PGE2 in the tumors, which potentially involves the MAPK pathway. These observations suggested the importance of COX-2 in lung tumorigenesis, especially under K-ras mutation and further identified COX-2 as a potential target in lung cancer prevention. The study is supported by NIH Grant R01CA144053. Citation Format: Yong Pan, Yan Jiang, Lin Tan, Murali K. Ravoori, Mihai Gagea-Iurascu, Mihai Gagea-Iurascu, Vikus Kundra, Susan M. Fischer, Peiying Yang. Genetic deletion of cyclooxygenase-2 suppresses K-ras induced lung tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 895. doi:10.1158/1538-7445.AM2015-895