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

  • Zhenhua Wu
  • Dan He
  • Shuyuan Zhao
  • Hongjiang WangEmail author


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.


IL-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.


  1. 1.
    Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A (2016) Cancer treatment and survivorship statistics, 2016. CA: Cancer J Clin 66(4):271–289. CrossRefGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA: Cancer J Clin 67(1):7–30. CrossRefGoogle Scholar
  3. 3.
    Vineis P, Wild CP (2014) Global cancer patterns: causes and prevention. Lancet 383(9916):549–557. CrossRefPubMedGoogle Scholar
  4. 4.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517. CrossRefPubMedGoogle Scholar
  5. 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. CrossRefPubMedGoogle Scholar
  6. 6.
    Ji Y, Zhang W (2010) Th17 cells: positive or negative role in tumor? Cancer Immunol Immunother 59(7):979–987. CrossRefPubMedGoogle Scholar
  7. 7.
    Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206(7):1457–1464. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hus I, Bojarska-Junak A, Chocholska S, Tomczak W, Wos J, Dmoszynska A, Rolinski J (2013) Th17/IL-17A might play a protective role in chronic lymphocytic leukemia immunity. PLoS ONE 8(11):e78091. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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
  11. 11.
    Huang Q, Du J, Fan J, Lv Z, Qian X, Zhang X, Han J, Chen C, Wu F, Jin Y (2014) The effect of proinflammatory cytokines on IL-17RA expression in NSCLC. Med Oncol 31(9):144. CrossRefPubMedGoogle Scholar
  12. 12.
    Jiang YX, Li PA, Yang SW, Hao YX, Yu PW (2015) Increased chemokine receptor IL-17RA expression is associated with poor survival in gastric cancer patients. Int J Clin Exp Pathol 8(6):7002–7008PubMedPubMedCentralGoogle Scholar
  13. 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. CrossRefPubMedGoogle Scholar
  14. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang M, Wang L, Ren T, Xu L, Wen Z (2013) IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells. Cancer Biol Ther 14(2):155–163. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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. CrossRefPubMedGoogle Scholar
  17. 17.
    Wang ZD, Huang C, Li ZF, Yang J, Li BH, Liang RR, Dai ZJ, Liu ZW (2010) Chrysanthemum indicum ethanolic extract inhibits invasion of hepatocellular carcinoma via regulation of MMP/TIMP balance as therapeutic target. Oncol Rep 23(2):413–421PubMedGoogle Scholar
  18. 18.
    Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hadler-Olsen E, Winberg JO, Uhlin-Hansen L (2013) Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 34(4):2041–2051. CrossRefPubMedGoogle Scholar
  20. 20.
    Liu J, Ping W, Zu Y, Sun W (2014) Correlations of lysyl oxidase with MMP2/MMP9 expression and its prognostic value in non-small cell lung cancer. Int J Clin Exp Pathol 7(9):6040–6047PubMedPubMedCentralGoogle Scholar
  21. 21.
    Greenberg AK, Basu S, Hu J, Yie TA, Tchou-Wong KM, Rom WN, Lee TC (2002) Selective p38 activation in human non-small cell lung cancer. Am J Respir Cell Mol Biol 26(5):558–564. CrossRefPubMedGoogle Scholar
  22. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhang Q, Liu S, Parajuli KR, Zhang W, Zhang K, Mo Z, Liu J, Chen Z, Yang S, Wang AR, Myers L, You Z (2017) Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition. Oncogene 36(5):687–699. CrossRefPubMedGoogle Scholar
  24. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Maeda S, Omata M (2008) Inflammation and cancer: role of nuclear factor-kappaB activation. Cancer Sci 99(5):836–842. CrossRefPubMedGoogle Scholar
  26. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang Y, Liu J, Kou J, Yu J, Yu B (2012) DT-13 suppresses MDA-MB-435 cell adhesion and invasion by inhibiting MMP-2/9 via the p38 MAPK pathway. Mol Med Rep 6(5):1121–1125. CrossRefPubMedGoogle Scholar
  28. 28.
    Kim ES, Kim MS, Moon A (2004) TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25(5):1375–1382PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Zhenhua Wu
    • 1
  • Dan He
    • 1
  • Shuyuan Zhao
    • 1
  • Hongjiang Wang
    • 1
    Email author
  1. 1.Department of Thoracic Surgery, Affiliated Tumor HospitalXinjiang Medical UniversityÜrümqiPeople’s Republic of China

Personalised recommendations