Original Article | Published:

Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition

Oncogene volume 36, pages 687699 (02 February 2017) | Download Citation

Abstract

Chronic inflammation has been associated with a variety of human cancers including prostate cancer. Interleukin-17 (IL-17) is a critical pro-inflammatory cytokine, which has been demonstrated to promote development of prostate cancer, colon cancer, skin cancer, breast cancer, lung cancer and pancreas cancer. IL-17 promotes prostate adenocarcinoma with a concurrent increase of matrix metalloproteinase 7 (MMP7) expression in mouse prostate. Whether MMP7 mediates IL-17’s action and the underlying mechanisms remain unknown. We generated Mmp7 and Pten double knockout (KO) (Mmp7−/−) mouse model and demonstrated that MMP7 promotes prostate adenocarcinoma through induction of epithelial-to-mesenchymal transition (EMT) in Pten-null mice. MMP7 disrupted E-cadherin/β-catenin complex to upregulate EMT transcription factors in mouse prostate tumors. IL-17 receptor C and Pten double KO mice recapitulated the weak EMT characteristics observed in Mmp7−/− mice. IL-17 induced MMP7 and EMT in human prostate cancer LNCaP, C4-2B and PC-3 cell lines, while small interfering RNA knockdown of MMP7 inhibited IL-17-induced EMT. Compound III, a selective MMP7 inhibitor, decreased development of invasive prostate cancer in Pten single KO mice. In human normal prostates and prostate tumors, IL-17 mRNA levels were positively correlated with MMP7 mRNA levels. These findings demonstrate that MMP7 mediates IL-17’s function in promoting prostate carcinogenesis through induction of EMT, indicating IL-17–MMP7–EMT axis as a potential target for developing new strategies in the prevention and treatment of prostate cancer.

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References

  1. 1.

    , . Inflammation and cancer. Nature 2002; 420: 860–867.

  2. 2.

    , , , . Asymptomatic inflammation and/or infection in benign prostatic hyperplasia. BJU Int 1999; 84: 976–981.

  3. 3.

    , , , , , et al. Distribution of chronic prostatitis in radical prostatectomy specimens with up-regulation of bcl-2 in areas of inflammation. J Urol 2002; 167: 2267–2270.

  4. 4.

    , , , , . Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density. Eur Urol 2000; 37: 404–412.

  5. 5.

    , , , . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 1999; 155: 1985–1992.

  6. 6.

    , , , , , et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007; 7: 256–269.

  7. 7.

    , . Inflammation in the etiology of prostate cancer: an epidemiologic perspective. Urol Oncol 2007; 25: 242–249.

  8. 8.

    , . Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology 2010; 129: 311–321.

  9. 9.

    , , , , , et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009; 15: 1016–1022.

  10. 10.

    , . IL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice. Biochem Biophys Res Commun 2011; 414: 31–36.

  11. 11.

    , , , , , . Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci USA 2010; 107: 5540–5544.

  12. 12.

    , , , , , . Role of IL-17A in the development of colitis-associated cancer. Carcinogenesis 2012; 33: 931–936.

  13. 13.

    , , , , , . IFNgamma promotes papilloma development by up-regulating Th17-associated inflammation. Cancer Res 2009; 69: 2010–2017.

  14. 14.

    , , , , . IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res 2010; 70: 10112–10120.

  15. 15.

    , , , , , et al. TGF-beta receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer Discov 2011; 1: 430–441.

  16. 16.

    , , , , , et al. Interleukin-17 promotes formation and growth of prostate adenocarcinoma in mouse models. Cancer Res 2012; 72: 2589–2599.

  17. 17.

    , , , , , et al. Interleukin-17 promotes development of castration-resistant prostate cancer potentially through creating an immunotolerant and pro-angiogenic tumor microenvironment. Prostate 2014; 74: 869–879.

  18. 18.

    , , , , , et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci USA 2014; 111: 5664–5669.

  19. 19.

    , , , , , et al. Promotion of lung tumor growth by interleukin-17. Am J Physiol Lung Cell Mol Physiol 2014; 307: L497–L508.

  20. 20.

    , , , , , et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 2014; 25: 621–637.

  21. 21.

    , . Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense. Immunol Rev 2014; 260: 129–144.

  22. 22.

    , , , , , et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal 2009; 2: ra63.

  23. 23.

    , . Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol 1996; 28: 123–136.

  24. 24.

    , , , , , . Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol 1991; 117: 144–150.

  25. 25.

    , , , , , et al. Matrilysin expression in human prostate carcinoma. Mol Carcinog 1996; 15: 57–63.

  26. 26.

    . Epithelial-mesenchymal transition. J Cell Sci 2005; 118: 4325–4326.

  27. 27.

    , , , . Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139: 871–890.

  28. 28.

    , , , , . Epithelial-to-mesenchymal transition in HPV-33-transfected cervical keratinocytes is associated with increased invasiveness and expression of gelatinase A. Int J Cancer 1994; 59: 661–666.

  29. 29.

    , . Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004; 118: 277–279.

  30. 30.

    , , , , , et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927–939.

  31. 31.

    , . Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818–829.

  32. 32.

    , , , , . Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci USA 1997; 94: 1402–1407.

  33. 33.

    , , , , , et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209–221.

  34. 34.

    , . In vitro and in vivo model systems used in prostate cancer research. J Biol Methods 2015; 2: e17 1–14.

  35. 35.

    , , , , , et al. Matrilysin stimulates DNA synthesis of cultured vascular endothelial cells and induces angiogenesis in vivo. Cancer Lett 2001; 173: 175–182.

  36. 36.

    , , , , , et al. MMP-7 (matrilysin) accelerated growth of human umbilical vein endothelial cells. Cancer Lett 2002; 177: 95–100.

  37. 37.

    , , , , , et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114: 111–118.

  38. 38.

    , , , , , . Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 1997; 139: 1861–1872.

  39. 39.

    , , . Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: a key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion. Clin Cancer Res 2001; 7: 3289–3297.

  40. 40.

    , , , , , . TNFalpha-mediated loss of beta-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells. PLoS One 2014; 9: e109868.

  41. 41.

    , . Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 2013; 27: 2192–2206.

  42. 42.

    , , , , , et al. The discovery of MMP7 inhibitors exploiting a novel selectivity trigger. ChemMedChem 2011; 6: 769–773.

  43. 43.

    , . The IL-17/IL-23 axis of inflammation in cancer: friend or foe? Curr Opin Investig Drugs 2009; 10: 543–549.

  44. 44.

    , . T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 2010; 10: 248–256.

  45. 45.

    , , , , , et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 1999; 59: 3698–3704.

  46. 46.

    , , , , , et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003; 101: 2620–2627.

  47. 47.

    , , , , , et al. Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology 2001; 61: 79–89.

  48. 48.

    , , , , , et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 2002; 99: 2114–2121.

  49. 49.

    , , , , , . IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 2009; 206: 1457–1464.

  50. 50.

    , , , , . Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 2009; 114: 357–359.

  51. 51.

    , , , , , et al. Interleukin-17-induced EMT promotes lung cancer cell migration and invasion via NF-kappaB/ZEB1 signal pathway. Am J Cancer Res 2015; 5: 1169–1179.

  52. 52.

    , , , , , et al. Effect of IL-17A on the migration and invasion of NPC cells and related mechanisms. PLoS One 2014; 9: e108060.

  53. 53.

    , , , , . Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc Natl Acad Sci USA 1998; 95: 14979–14984.

  54. 54.

    , , , . Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 2003; 124: 392–400.

  55. 55.

    , , , , , et al. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J Cell Biol 2001; 152: 87–96.

  56. 56.

    , , , , , et al. Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J Cell Biol 2002; 157: 429–440.

  57. 57.

    , , , , , et al. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 2003; 63: 3145–3153.

  58. 58.

    , , , , , et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res 2004; 64: 2270–2305.

  59. 59.

    , , , , , et al. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis. Drug Des Devel Ther 2013; 7: 635–643.

  60. 60.

    , , , , , et al. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44-VCAM-1 interaction. Prostate 2015; 75: 883–895.

  61. 61.

    , , , , , et al. Hyperinsulinemia enhances interleukin-17-induced inflammation to promote prostate cancer development in obese mice through inhibiting glycogen synthase kinase 3-mediated phosphorylation and degradation of interleukin-17 receptor. Oncotarget 2016; 7: 13651–13666.

  62. 62.

    , , , , , et al. MapSplice: accurate mapping of RNA-seq reads for splice junction discovery. Nucleic Acids Res 2010; 38: e178.

  63. 63.

    , , , , . RNA-Seq gene expression estimation with read mapping uncertainty. Bioinformatics 2010; 26: 493–500.

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Acknowledgements

ZY was partially supported by the National Institutes of Health (R01CA174714 and P20GM103518), Department of Defense (W81XWH-14-1-0050, W81XWH-14-1-0149, W81XWH-14-1-0458 (PI: Feng Chen; Co-I: ZY), and W81XWH-15-1-0444), the Developmental Fund of Tulane Cancer Center (TCC), Louisiana Cancer Research Consortium (LCRC) Fund and Tulane’s Institute of Integrated Engineering for Health and Medicine (TI2EHM). WZ and KZ were partially supported by the National Institute on Minority Health and Health Disparities (5G12MD007595, PIs: Gene D’Amour and Guangdi Wang).

Author information

Author notes

    • Q Zhang
    •  & S Liu

    These authors contributed to this work equally.

Affiliations

  1. Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA

    • Q Zhang
    • , S Liu
    • , K R Parajuli
    • , Z Mo
    • , J Liu
    • , Z Chen
    • , S Yang
    •  & Z You
  2. Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA

    • W Zhang
    •  & K Zhang
  3. Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, China

    • Z Mo
    •  & J Liu
  4. Department of Thoracic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, China

    • Z Chen
  5. Department of Urology, The Third Hospital of Hebei Medical University, Shijiazhuang, China

    • S Yang
  6. Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA

    • A R Wang
  7. Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA, USA

    • L Myers
  8. Department of Orthopaedic Surgery, Tulane University, New Orleans, LA, USA

    • Z You
  9. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University, New Orleans, LA, USA

    • Z You
  10. Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA, USA

    • Z You
  11. Tulane Center for Aging, Tulane University, New Orleans, LA, USA

    • Z You

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The authors declare no conflict of interest.

Corresponding author

Correspondence to Z You.

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DOI

https://doi.org/10.1038/onc.2016.240

Supplementary Information accompanies this paper on the Oncogene website (http://www.nature.com/onc)

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