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IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer

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Abstract

The present study is to investigate the effect and mechanism of action of interleukin (IL)-17A and its receptor IL-17RA on non-small cell lung cancer (NSCLC). A total of 139 NSCLC patients were included in the study. NSCLC tissues and tumor-adjacent tissues were collected from the patients. Human NSCLC cell lines H157, H1975, and A549 were used for in vitro studies. MTT assay was performed to determine cell proliferation. Wound healing assay was used to determine cell motility. Transwell assay was carried out to detect migration and invasion. Quantitative real-time polymerase chain reaction was conducted to measure mRNA expression, while Western blotting was used for determine protein expression. Immunohistochemistry was employed to evaluate IL-17RA expression in 139 primary human NSCLC tissues. Levels of IL-17RA in NSCLC tissues were higher than tumor-adjacent normal tissues, and associated with clinical outcomes. Kaplan–Meier survival analysis indicated that NSCLC patients with positive IL-17RA expression had a poor survival. In addition, IL-17A/IL-17RA affected NSCLC cell migration and invasion in vitro. Treatment with IL-17A/IL-17RA increased the expression of MMP-2 and MMP-9 in NSCLC cells. Furthermore, phosphorylation of p38 was enhanced in IL-17RA-overexpressing NSCLC cells. P38 MAPK-specific inhibitor SB203580 suppressed the migration and invasion of NSCLC cells. MMP-2 and MMP-9 were downstream effectors of IL-17RA and p38 signaling pathways. The present study demonstrates that P38 MAPK activity is crucial for IL-17A/IL-17RA to promote NSCLC metastasis. In addition, IL-17A/IL-17RA signaling may be a novel and promising cancer therapeutic target for the treatment of NSCLC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81460354) and Xinjiang Uygur Autonomous Region Natural Science Foundation (No. 2018D01C266).

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  1. Zhenhua Wu and Dan He are equally contributed to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Affiliated Tumor Hospital, Xinjiang Medical University, No. 789 East Suzhou Road, Ürümqi, 830000, Xinjiang Uygur Autonomous Region, People’s Republic of China

    Zhenhua Wu, Dan He, Shuyuan Zhao & Hongjiang Wang

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  1. Zhenhua Wu
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  2. Dan He
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  4. Hongjiang Wang
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Correspondence to Hongjiang Wang.

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Wu, Z., He, D., Zhao, S. et al. IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer. Mol Cell Biochem 455, 195–206 (2019). https://doi.org/10.1007/s11010-018-3483-9

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