Tumor Biology

, Volume 37, Issue 8, pp 11127–11134 | Cite as

IL-33 is associated with unfavorable postoperative survival of patients with clear-cell renal cell carcinoma

  • Zewei Wang
  • Le Xu
  • Yuan Chang
  • Lin Zhou
  • Hangcheng Fu
  • Weijuan Zhang
  • Yuanfeng Yang
  • Jiejie Xu
Original Article


The aim of this study was to evaluate the potential prognostic significance of interleukin-33 (IL-33) in patients with clear-cell renal cell carcinoma (ccRCC) after surgical resection. In this retrospective research, we enrolled 203 patients with ccRCC undergoing nephrectomy between 2003 and 2004 in a single institution. We recorded clinicopathologic features, overall survival (OS), and recurrence-free survival (RFS) and assessed IL-33 expression by immunohistochemical staining. On such bases, the correlations between IL-33 expression and clinicopathologic features and prognosis were evaluated. A high expression of IL-33 was significantly associated with advanced TNM stage and Fuhrman grade (p = 0.017 and p < 0.001, respectively) in patients with ccRCC. Moreover, multivariate analysis identified IL-33 as an independent prognostic factor of OS for patients with ccRCC after surgery (hazard ratio = 2.050; 95 % CI 1.223–3.447; p = 0.006). The incorporation of IL-33 into the TNM stage and Fuhrman grade might help to refine individual risk stratification. The IL-33 expression may serve as an independent negative predictor of survival for patients with ccRCC after surgery.


Clear-cell renal cell carcinoma Interleukin-33 Prognostic biomarker Overall survival 



This study was funded by grants from the National Basic Research Program of China (2012CB822104), National Key Projects for Infectious Diseases of China (2012ZX10002012-007, 2016ZX10002018-008), National Natural Science Foundation of China (31100629, 31270863, 81372755, 31470794, 81401988, 81402082, 81402085, 81471621, 81472227, 81472376, 31570803, 81501999, and 81572352), and Program for New Century Excellent Talents in University (NCET-13-0146). All these study sponsors have no roles in the study design, in the collection, analysis, and interpretation of data.

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2016_4879_Fig5_ESM.gif (17 kb)
Figure S1

Kaplan-Meier analysis of OS in patients with TNM stage III (a) and stage IV (b) based on the expression of IL-33. Kaplan-Meier analysis of RFS in patients with T3-4N0M0 (c). P value was calculated by log-rank test. (GIF 16 kb)

13277_2016_4879_MOESM1_ESM.tif (466 kb)
High Resolution Image (TIF 466 kb)


  1. 1.
    Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60:615–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Oosterwijk E, Rathmell WK, Junker K, Brannon AR, Pouliot F, Finley DS, et al. Basic research in kidney cancer. Eur Urol. 2011;60:622–33.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193–205.CrossRefPubMedGoogle Scholar
  4. 4.
    Lang H, Lindner W, de Fromont M, Molinie V, Letourneux H, Meyer N, et al. Multicenter determination of optimal interobserver agreement using the Fuhrman grading system for renal cell carcinoma—assessment of 241 patients with >15-year follow-up. Cancer. 2005;103:625–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Zisman A. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20:4559–66.CrossRefPubMedGoogle Scholar
  6. 6.
    Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol. 2002;168:2395–400.CrossRefPubMedGoogle Scholar
  7. 7.
    Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol. 2011;60:644–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Jovanovic IP, Pejnovic NN, Radosavljevic GD, Arsenijevic NN, Lukic ML. IL-33/ST2 axis in innate and acquired immunity to tumors. Oncoimmunol. 2012;1:229–31.CrossRefGoogle Scholar
  9. 9.
    Zhao Q, Chen G. Role of IL-33 and its receptor in T cell-mediated autoimmune diseases. BioMed Res Int. 2014;2014:587376.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Jiang HR, Milovanovic M, Allan D, Niedbala W, Besnard AG, Fukada SY, et al. IL-33 attenuates EAE by suppressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur J Immunol. 2012;42:1804–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Schmitz J, Owyang A, Oldham E, Song YL, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Miller AM. Role of IL-33 in inflammation and disease. J Inflamm. 2011;8:22.CrossRefGoogle Scholar
  13. 13.
    Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3, e3331.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Choi YS, Choi HJ, Min JK, Pyun BJ, Maeng YS, Park H, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood. 2009;114:3117–26.CrossRefPubMedGoogle Scholar
  15. 15.
    Joshi AD, Oak SR, Hartigan AJ, Finn WG, Kunkel SL, Duffy KE, et al. Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages. BMC Immunol. 2010;11:52.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Masamune A, Watanabe T, Kikuta K, Satoh K, Kanno A, Shimosegawa T. Nuclear expression of interleukin-33 in pancreatic stellate cells. Am J Physiol-Gastr L. 2010;299:G821–32.Google Scholar
  17. 17.
    Bergis D, Kassis V, Ranglack A, Koeberle V, Piiper A, Kronenberger B, et al. High serum levels of the interleukin 33 receptor soluble ST2 as a negative prognostic factor in hepatocellular carcinoma. J Hepatol. 2013;58:S257–7.CrossRefGoogle Scholar
  18. 18.
    Jovanovic IP, Pejnovic NN, Radosavljevic GD, Pantic JM, Milovanovic MZ, Arsenijevic NN, et al. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int J Cancer J Int Du Cancer. 2014;134:1669–82.CrossRefGoogle Scholar
  19. 19.
    Hu L-A, Fu Y, Zhang D-N, Zhang J. Serum IL-33 as a diagnostic and prognostic marker in non-small cell lung cancer. Asian Pac J Cancer Prev. 2013;14:2563–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.CrossRefPubMedGoogle Scholar
  21. 21.
    Pajares MJ, Agorreta J, Larrayoz M, Vesin A, Ezponda T, Zudaire I, et al. Expression of tumor-derived vascular endothelial growth factor and its receptors is associated with outcome in early squamous cell carcinoma of the lung. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:1129–36.CrossRefGoogle Scholar
  22. 22.
    Mager LF, Riether C, Schurch CM, Banz Y, Wasmer MH, Stuber R, et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J Clin Invest. 2015;125:2579–91.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yu XX, Hu Z, Shen X, Dong LY, Zhou WZ, Hu WH. IL-33 promotes gastric cancer cell invasion and migration via ST2-ERK1/2 pathway. Dig Dis Sci. 2015;60:1265–72.CrossRefPubMedGoogle Scholar
  24. 24.
    Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7:827–40.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Jovanovic I, Radosavljevic G, Mitrovic M, Juranic VL, McKenzie AN, Arsenijevic N, et al. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur J Immunol. 2011;41:1902–12.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Zewei Wang
    • 1
  • Le Xu
    • 2
  • Yuan Chang
    • 3
  • Lin Zhou
    • 3
  • Hangcheng Fu
    • 1
  • Weijuan Zhang
    • 4
  • Yuanfeng Yang
    • 3
  • Jiejie Xu
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, School of Basic Medical SciencesFudan UniversityShanghaiChina
  2. 2.Department of Urology, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
  3. 3.Department of Urology, Zhongshan HospitalFudan UniversityShanghaiChina
  4. 4.Department of Immunology, School of Basic Medical SciencesFudan UniversityShanghaiChina

Personalised recommendations