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S100A8/A9-RAGE pathway and chronic airway inflammation in smoke-induced lung carcinogenesis

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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. The RAGE-ligand axis (HMGB1, S100A8/A9) contributes to cigarette smoke-induced persistent and progressive inflammation. The aim of the present study was to determine the inflammatory effect on the S100A8/A9-RAGE pathway in smoke-induced lung cancer carcinogenesis.

Methods

Human alveolar adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B) were co-cultured for 24 h with PBMCs and then were incubated in the presence or absence of 1.5% cigarette smoke extract (CSE) for 24 h. The cells were then transfected with siRNA targeting S100A8/9 or RAGE. Cell viability, colony-forming ability, migration, invasion, metastasis, and morphological changes were assessed. Female A/J mice were given benzo(a)pyrene (B(a)P; 100 mg/kg) in 0.1 mL of corn oil via oral gavage once a week for 3 weeks and administrated CSE (1.25 ul/g) intratracheally twice a week for 4 weeks. Tumor load was determined by averaging the total tumor volume in each group. Bronchoalveolar lavage (BAL) cells were differentiated and counted to analyze inflammatory cells present.

Results

Cell growth and colony formation were promoted by exposure to CSE and significantly inhibited by S100A8/9 and RAGE-siRNA transfection, especially in A549 cells compared to BEAS-2B cells. Cell migration, invasion, MMP-2/9 activity, and the mRNA and protein expression of TLR4, NF-κB, RAGE, S100A8/9, and HMBG1 were increased in CSE-exposed A549 cells. S100A8/9 and RAGE-siRNA transfection significantly attenuated those expressions. B(a)P induced an average tumor volume of 7.28 mm3 per mouse, and CSE significantly increased the tumor volume (8.10 mm3) compared to the B(a)P group. The total cell number and lymphocytes in BAL fluid tended to increase after CSE administration in the lung cancer mouse group. Moreover, CSE significantly induced the levels of S100A8/9, RAGE, p38, and ERK, and decreased JNK in serum and tumors compared to adjacent lung tissues (p < 0.05).

Conclusion

Our study suggests that the S100A8/A9-RAGE signal pathway is the mainstream of the inflammation-immune response induced in cancer progression in CSE-related smoke-induced lung carcinogenesis in vitro and in vivo. Further studies are needed to identify the therapeutic targets of cigarette smoke-induced inflammation and immunosuppression in the tumor microenvironment.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PBMC:

Peripheral blood mononuclear cell

TLR4:

Toll-like receptor 4

NF-κB:

Nuclear factor kappa-light-chain enhancer of activated B cells

RAGE:

Receptor for advanced glycation end products

HMBG1:

High mobility group box 1

ERK:

Extracellular signal-regulated kinase

JNK:

C-Jun N-terminal kinase

MMP:

Matrix metalloproteinase

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Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1F1A1066281).

Funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1F1A1066281).

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Author notes

  1. Sung Bae Cho and In Kyoung Kim contributed equally to this work.

Authors and Affiliations

  1. Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Sung Bae Cho, In Kyoung Kim, Hye Seon Kang, Sang Haak Lee & Chang Dong Yeo

  2. College of Medicine, Cancer Research Institute, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    In Kyoung Kim & Sang Haak Lee

  3. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, 1021, Tongil Ro, Eunpyeong-gu, Seoul, Republic of Korea

    Sang Haak Lee & Chang Dong Yeo

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Correspondence to Sang Haak Lee or Chang Dong Yeo.

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Conflicts of interest

Sung Bae Cho declares that he/she has no conflict of interest. In Kyoung declares that he/she has no conflict of interest. Hye Seon Kang declares that he/she has no conflict of interest. Sang Haak Lee that he/she has no conflict of interest. Chang Dong Yeo declares that he/she has no conflict of interest.

Ethical approval

This study was approved by the Ethical Committee on Animal Experiments of the Catholic University of Korea (EPSMH-2020-30-02-H).

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Cho, S.B., Kim, I.K., Kang, H.S. et al. S100A8/A9-RAGE pathway and chronic airway inflammation in smoke-induced lung carcinogenesis. Mol. Cell. Toxicol. 20, 177–186 (2024). https://doi.org/10.1007/s13273-023-00339-0

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