Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer

  • Authors:
    • Qiongying Lv
    • Kejia Wu
    • Fulin Liu
    • Wanrong Wu
    • Yurou Chen
    • Wei Zhang
  • View Affiliations

  • Published online on: July 26, 2018     https://doi.org/10.3892/ijo.2018.4503
  • Pages: 1809-1817
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Interleukin‑17A (IL‑17A) is a CD4 T-cell-derived pro-inflammatory cytokine that is involved in human cervical tumorigenesis. Heparanase (HPSE) is an endo-glycosidase expressed in mammals, which has been confirmed to be associated with cervical cancer invasion. In the present study, it was hypothesized that IL‑17A and HPSE are key proteins promoting tumor angiogenesis and cell proliferation and invasion in cervical cancer. The expression of IL‑17A and HPSE in cervical cancer tissues was detected by immunohistochemical staining. In addition, the expression of IL‑17A and HPSE was down- and upregulated via RNAi and human recombinant proteins, and MTT and Transwell assays were performed to examine cervical cancer cell proliferation and invasion, respectively. Flow cytometry analysis was also performed to detect cell cycle distribution, and the levels of target mRNA and protein were evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. IL‑17A and HPSE were highly expressed in cervical cancer tissues, and microvessel density was notably higher in the IL‑17A-positive group. IL‑17A and/or HPSE recombinant protein promoted the proliferation and invasion of cervical cancer cells, increased the proportion of cells in the G2/M phase, and enhanced the mRNA and protein expression of human papillomavirus E6, P53, vascular endothelial growth factor and CD31, whereas downregulation of IL‑17A and/or HPSE exerted the opposite effects. Furthermore, downregulation of IL‑17A and/or HPSE was found to inhibit the expression of nuclear factor (NF)-κB P65. In summary, IL‑17A and HPSE may promote tumor angiogenesis and cell proliferation and invasion in cervical cancer, possibly via the NF-κB signaling pathway. These findings may lead to the identification of new diagnostic markers and therapeutic targets.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK and Armitage RJ: Human IL-17: A novel cytokine derived from T cells. J Immunol. 155:5483–5486. 1995.PubMed/NCBI

3 

Gaffen SL: An overview of IL-17 function and signaling. Cytokine. 43:402–407. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Gerhardt S, Abbott WM, Hargreaves D, Pauptit RA, Davies RA, Needham MR, Langham C, Barker W, Aziz A, Snow MJ, et al: Structure of IL-17A in complex with a potent, fully human neutralizing antibody. J Mol Biol. 394:905–921. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Omrane I, Medimegh I, Baroudi O, Ayari H, Bedhiafi W, Stambouli N, Ferchichi M, Kourda N, Bignon YJ, Uhrhammer N, et al: Involvement of IL17A, IL17F and IL23R polymorphisms in colorectal cancer therapy. PLoS One. 10:e01289112015. View Article : Google Scholar : PubMed/NCBI

6 

Xu B, Guenther JF, Pociask DA, Wang Y, Kolls JK, You Z, Chandrasekar B, Shan B, Sullivan DE and Morris GF: Promotion of lung tumor growth by interleukin-17. Am J Physiol Lung Cell Mol Physiol. 307:L497–L508. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Slattery ML, Herrick JS, Torres-Mejia G, John EM, Giuliano AR, Hines LM, Stern MC, Baumgartner KB, Presson AP and Wolff RK: Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: The Breast Cancer Health Disparities Study. Carcinogenesis. 35:1750–1759. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Dai ZM, Zhang TS, Lin S, Zhang WG, Liu J, Cao XM, Li HB, Wang M, Liu XH, Liu K, et al: Role of IL-17A rs2275913 and IL-17F rs763780 polymorphisms in risk of cancer development: An updated meta-analysis. Sci Rep. 6:204392016. View Article : Google Scholar : PubMed/NCBI

9 

Gomes AL, Teijeiro A, Burén S, Tummala KS, Yilmaz M, Waisman A, Theurillat JP, Perna C and Djouder N: Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 30:161–175. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, Moghaddam SJ and Dong C: T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci USA. 111:5664–5669. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Lin WW and Karin M: A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 117:1175–1183. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Tong Z, Yang XO, Yan H, Liu W, Niu X, Shi Y, Fang W, Xiong B, Wan Y and Dong C: A protective role by interleukin-17F in colon tumorigenesis. PLoS One. 7:e349592012. View Article : Google Scholar : PubMed/NCBI

13 

Kulig P, Burkhard S, Mikita-Geoffroy J, Croxford AL, Hövelmeyer N, Gyülvészi G, Gorzelanny C, Waisman A, Borsig L and Becher B: IL17A-mediated endothelial breach promotes metastasis formation. Cancer Immunol Res. 4:26–32. 2016. View Article : Google Scholar

14 

Meirovitz A, Goldberg R, Binder A, Rubinstein AM, Hermano E and Elkin M: Heparanase in inflammation and inflammation-associated cancer. FEBS J. 280:2307–2319. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N and Elkin M: Significance of heparanase in cancer and inflammation. Cancer Microenviron. 5:115–132. 2012. View Article : Google Scholar :

16 

Boyango I, Barash U, Naroditsky I, Li JP, Hammond E, Ilan N and Vlodavsky I: Heparanase cooperates with Ras to drive breast and skin tumorigenesis. Cancer Res. 74:4504–4514. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Fernandes dos Santos TC, Gomes AM, Paschoal ME, Stelling MP, Rumjanek VM, Junior AR, Valiante PM, Madi K, Pereira de Souza HS, Pavão MS, et al: Heparanase expression and localization in different types of human lung cancer. Biochim Biophys Acta. 1840:2599–2608. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Poon IK, Goodall KJ, Phipps S, Chow JD, Pagler EB, Andrews DM, Conlan CL, Ryan GF, White JA, Wong MK, et al: Mice deficient in heparanase exhibit impaired dendritic cell migration and reduced airway inflammation. Eur J Immunol. 44:1016–1030. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Shteingauz A, Boyango I, Naroditsky I, Hammond E, Gruber M, Doweck I, Ilan N and Vlodavsky I: Heparanase enhances tumor growth and chemoresistance by promoting autophagy. Cancer Res. 75:3946–3957. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Lv Q, Zhu D, Zhang J, Yi Y, Yang S and Zhang W: Association between six genetic variants of IL-17A and IL-17F and cervical cancer risk: A case-control study. Tumour Biol. 36:3979–3984. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Lü QY, Zhang W, Cheng J, Zhang WT and Zhong YJ: Effect on invasion ability of cervical cancer cells after silence heparanase gene expression in HeLa cells. Zhonghua Fu Chan Ke Za Zhi. 48:532–537. 2013.In Chinese.

22 

Chen RJ, Shun CT, Yen ML, Chou CH and Lin MC: Methyltransferase G9a promotes cervical cancer angiogenesis and decreases patient survival. Oncotarget. 8:62081–62098. 2017.PubMed/NCBI

23 

Li X, Song Y, Liu F, Liu D, Miao H, Ren J, Xu J, Ding L, Hu Y, Wang Z, et al: Long non-coding RNA MALAT1 promotes proliferation, angiogenesis, and immunosuppressive properties of mesenchymal stem cells by inducing VEGF and IDO. J Cell Biochem. 118:2780–2791. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Zhu X, Er K, Mao C, Yan Q, Xu H, Zhang Y, Zhu J, Cui F, Zhao W and Shi H: miR-203 suppresses tumor growth and angiogenesis by targeting VEGFA in cervical cancer. Cell Physiol Biochem. 32:64–73. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Fernandes JV, DE Medeiros Fernandes TA, DE Azevedo JC, Cobucci RN, DE Carvalho MG, Andrade VS and DE Araújo JM: Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review). Oncol Lett. 9:1015–1026. 2015. View Article : Google Scholar : PubMed/NCBI

26 

He G and Karin M: NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21:159–168. 2011. View Article : Google Scholar

27 

Vreys V and David G: Mammalian heparanase: What is the message? J Cell Mol Med. 11:427–452. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Chang YH, Yu CW, Lai LC, Tsao CH, Ho KT, Yang SC, Lee H, Cheng YW, Wu TC and Shiau MY: Up-regulation of interleukin-17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancer. Cancer. 116:4800–4809. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Hirshoren N, Bulvik R, Neuman T, Rubinstein AM, Meirovitz A and Elkin M: Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma. J Cell Mol Med. 18:181–186. 2014. View Article : Google Scholar :

30 

Bowers JS, Nelson MH, Kundimi S, Bailey SR, Huff LW, Schwartz KM, Cole DJ, Rubinstein MP and Paulos CM: Dendritic cells in irradiated mice trigger the functional plasticity and antitumor activity of adoptively transferred Tc17 cells via IL12 signaling. Clin Cancer Res. 21:2546–2557. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Yan B, Liu Y, Bai H, Chen M, Xie S, Li D, Liu M and Zhou J: HDAC6 regulates IL-17 expression in T lymphocytes: Implications for HDAC6-targeted therapies. Theranostics. 7:1002–1009. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S and Roden RB: Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res. 15:570–577. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E and Ben-Neriah Y: NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 431:461–466. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2018
Volume 53 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Lv, Q., Wu, K., Liu, F., Wu, W., Chen, Y., & Zhang, W. (2018). Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer. International Journal of Oncology, 53, 1809-1817. https://doi.org/10.3892/ijo.2018.4503
MLA
Lv, Q., Wu, K., Liu, F., Wu, W., Chen, Y., Zhang, W."Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer". International Journal of Oncology 53.4 (2018): 1809-1817.
Chicago
Lv, Q., Wu, K., Liu, F., Wu, W., Chen, Y., Zhang, W."Interleukin‑17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer". International Journal of Oncology 53, no. 4 (2018): 1809-1817. https://doi.org/10.3892/ijo.2018.4503