Abstract 3947: S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis

Abstract Background: Cigarette smoke-induced chronic airway inflammation increases the risk of lung cancer, and plays a multifaceted role in lung cancer initiation and progression, and RAGE-ligand axis (HMGB1, S100A8/A9) contributes Cigarette smoke-induced persistent and progressive inflammation. The aim of the present study was to determine the inflammatory effect on S100A8/A9-RAGE pathway in smoke-induced carcinogenesis in lung cancer. Methods: Human alveolar adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B) were co-cultured for 24 h with the PBMC and then, cells were incubated in the presence or absence of 1.5% cigarette smoke extract (CSE) for 24 h. The cells transfected with siRNA targeting S100A8/9 or RAGE. The cell viability, colony-forming ability, migration, invasion, metastasis and morphological changes were assessed. Female A/J mice were given a benzo(a)pyrene (100mg/kg) in 0.1 ml corn oil via oral gavage at once a week for 3 weeks, and administrated CSE (1.25 ul/g) via intratracheal (IT) at twice a week for 4 weeks. Tumor load was determined by averaging the total tumor volume in each group. BAL differential cells were counted to analyze inflammatory cells. Results: Cellular growth and colony-forming were promoted by exposure to CSE, and significantly inhibited by S100A8/9 and RAGE-siRNA transfection, especially in A549 cells than BEAS-2B. Cell migration, invasion, MMP-2/9 activities, and the mRNA and protein expression of TLR4, NF-κB, RAGE, S100A8/9 and HMBG1 were higher in CSE exposed A549 cells. S100A8/9 and RAGE-siRNA transfection attenuated those expression, significantly. B(a)P induced an average tumor volume 7.28 mm3 per mouse, and CSE significantly increased tumor volume (8.10 mm3) compared to the B(a)P group. The total cell number and lymphocytes in BAL fluids tended to increase after CSE administration in lung cancer mouse group. Moreover, CSE significantly induced the levels of S100A8/9 and RAGE, p38 and p-ERK, and decreased JNK in serum and tumors with adjacent lung tissues (p < 0.05). Conclusions: We identified cigarette smoke-induced S100A8/A9-RAGE pathway promoted airway inflammation and lung carcinogenesis in vitro and in vivo. Although S100A8/A9 protein contributes to many types of disease, this study will help us gain a better understanding of the complexities of cancer progression. Further studies are needed for therapeutic target of cigarette smoke-induced inflammation and immunosuppression in tumor microenviornment. Citation Format: Hye Seon Kang, In Kyoung Kim, Chang Dong Yeo, Jin Woo Kim, Sang Haak Lee. S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3947.