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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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.
KeywordsIL-17A/IL-17RA MMP-2 MMP-9 P38 MAPK signaling pathway Non-small cell lung cancer
This work was supported by the National Natural Science Foundation of China (No. 81460354) and Xinjiang Uygur Autonomous Region Natural Science Foundation (No. 2018D01C266).
Compliance with ethical standards
Conflict of interest
All authors declare no financial competing interests. All authors declare no non-financial competing interests.
- 4.Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517. https://doi.org/10.1146/annurev.immunol.021908.132710 CrossRefPubMedGoogle Scholar
- 5.Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852. https://doi.org/10.1146/annurev.immunol.25.022106.141557 CrossRefPubMedGoogle Scholar
- 8.Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, Pan JF, Yan J, Hu JH, Wang Z, Dai Z, Fan J, Zhou J (2011) IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer 10:150. https://doi.org/10.1186/1476-4598-10-150 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Wright JF, Bennett F, Li B, Brooks J, Luxenberg DP, Whitters MJ, Tomkinson KN, Fitz LJ, Wolfman NM, Collins M, Dunussi-Joannopoulos K, Chatterjee-Kishore M, Carreno BM (2008) The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol 181(4):2799–2805CrossRefGoogle Scholar
- 13.Liu Y, Zhao X, Sun X, Li Y, Wang Z, Jiang J, Han H, Shen W, Corrigan CJ, Sun Y (2015) Expression of IL-17A, E, and F and their receptors in human prostatic cancer: comparison with benign prostatic hyperplasia. Prostate 75(16):1844–1856. https://doi.org/10.1002/pros.23058 CrossRefPubMedGoogle Scholar
- 14.Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, Zhang W, Zhong Z, Sanchez-Lopez E, Wu LW, Taniguchi K, Feng Y, Fearon E, Grivennikov SI, Karin M (2014) Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41(6):1052–1063. https://doi.org/10.1016/j.immuni.2014.11.009 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Asukai K, Kawamoto K, Eguchi H, Konno M, Nishida N, Koseki J, Noguchi K, Hasegawa S, Ogawa H, Yamada D, Tomimaru Y, Tomokuni A, Asaoka T, Noda T, Wada H, Gotoh K, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H (2015) Prognostic impact of peritumoral IL-17-positive cells and IL-17 Axis in patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol 22(Suppl 3):S1524–S1531. https://doi.org/10.1245/s10434-015-4782-y CrossRefPubMedGoogle Scholar
- 22.Kato S, Yokoyama S, Hayakawa Y, Li L, Iwakami Y, Sakurai H, Saiki I (2016) P38 pathway as a key downstream signal of connective tissue growth factor to regulate metastatic potential in non-small-cell lung cancer. Cancer Sci 107(10):1416–1421. https://doi.org/10.1111/cas.13009 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Li J, Lau GK, Chen L, Dong SS, Lan HY, Huang XR, Li Y, Luk JM, Yuan YF, Guan XY (2011) Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression. PLoS One 6(7):e21816. https://doi.org/10.1371/journal.pone.0021816 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Kwon HC, Kim SH, Oh SY, Lee S, Lee JH, Jang JS, Kim MC, Kim KH, Kim SJ, Kim SG, Kim HJ (2012) Clinicopathologic significance of expression of nuclear factor-kappaB RelA and its target gene products in gastric cancer patients. World J Gastroenterol 18(34):4744–4750. https://doi.org/10.3748/wjg.v18.i34.4744 CrossRefPubMedPubMedCentralGoogle Scholar