Abstract
Although lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a KrasG12D/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer.
Highlights
Lung cancer is the leading cause of cancer-related deaths among both men and women, with more than 1.5 million deaths per year worldwide[1]
The levels of phosphorylated cytosolic phospholipase A2 (p-cPLA2), 5-LOX, 12-LOX, and BLT2 were strongly enhanced in the lung tissues of the KrasG12D mice compared with those of the WT mice. These results suggest that the expression of members of the p-cPLA2-5-/12-LOX-BLT2 cascade is upregulated in the KrasG12D-driven lung cancer mouse model
Our results indicate that BLT2 has a potential role in KRAS-driven lung cancer
Summary
Lung cancer is the leading cause of cancer-related deaths among both men and women, with more than 1.5 million deaths per year worldwide[1]. Epidermal growth factor receptor (EGFR) mutations are the second most common cause of lung cancer, and KRAS is the most frequently mutated oncogene in lung cancer cases[2]. Despite several notable studies[3,4], mutant KRAS is difficult to target with small molecules due to its undruggable structure[5]. Because of these limitations, alternative approaches involving lung inflammatory pathways have been explored[6]. Interleukin-6 (IL-6) is a proinflammatory cytokine that has been implicated in the progression of lung cancers, including KRAS-driven lung cancer[7]. IL-6 blockade has limited effectiveness in lung cancer patients[11,12], and alternative molecular targets are required
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