Open Access

Interleukin‑35 is associated with the tumorigenesis and progression of prostate cancer

  • Authors:
    • Jialin Zhu
    • Xueling Yang
    • Yan Wang
    • Haonan Zhang
    • Zhi Guo
  • View Affiliations

  • Published online on: April 3, 2019     https://doi.org/10.3892/ol.2019.10208
  • Pages: 5094-5102
  • Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Interleukin (IL)‑35 is a novel member of the IL‑12 cytokine family, which exhibits a unique immune regulatory function. Previously, it was demonstrated that IL‑35 expression is significantly increased in a wide range of tumor tissues, promoting angiogenesis and inhibiting the anti‑tumor immune response. In the present study, the IL‑35 protein expression levels were measured in the plasma and tumor tissue of patients with prostate cancer (PCA), and its role was determined in the occurrence and progression of PCA. Plasma IL‑35 expression levels were measured using ELISA, and the associations of plasma IL‑35 and clinicopathological parameters were analyzed. Receiver operating characteristic curves were plotted to analyze the role of IL‑35 as a clinical biomarker for the diagnosis of PCA. Survival curve analysis demonstrated a significant decrease in the survival time in months in patients with PCA and increased expression levels of IL‑35 compared with the participants with relatively lower IL‑35 protein expression levels. IL‑35 expression was detected using immunohistochemical staining of a human PCA tissue microarray. Plasma IL‑35 expression levels in the patients with PCA were significantly increased compared with the patients with benign prostatic hyperplasia and the healthy controls. An increase in the plasma concentration of IL‑35 was associated with progression of PCA stage and an increase in the Gleason score. Significant differences in AUCs for IL‑35 and prostate‑specific antigen were observed with regard to the presence of lymph node and distant metastases in patients with PCA. The expression levels of Epstein‑barr virus‑induced gene 3 (EBI3) and IL‑12A (p35; the subunits which together form IL‑35) were significantly increased in the tumor tissue compared with the adjacent normal tissue. An association was identified between the Gleason score and the expression of EBI3 and p35. Therefore, increased expression of IL‑35 in the plasma and tumor tissues may contribute to the progression and metastasis of PCA, and IL‑35 may serve as a novel prognostic biomarker or therapeutic target for the treatment of PCA.

References

1 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Lilja H, Ulmert D and Vickers AJ: Prostate-specific antigen and prostate cancer: Prediction, detection and monitoring. Nat Rev Cancer. 8:268–278. 2008. View Article : Google Scholar : PubMed/NCBI

3 

Shariat SF, Semjonow A, Lilja H, Savage C, Vickers AJ and Bjartell A: Tumor markers in prostate cancer I: Blood-based markers. Acta Oncol. 50 (Suppl 1):S61–S75. 2011. View Article : Google Scholar

4 

Hwang JE, Joung JY, Shin SP, Choi MK, Kim JE, Kim YH, Park WS, Lee SJ and Lee KH: Ad5/35E1aPSESE4: A novel approach to marking circulating prostate tumor cells with a replication competent adenovirus controlled by PSA/PSMA transcription regulatory elements. Cancer Lett. 372:57–64. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Cooperberg MR, Broering JM and Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 28:1117–1123. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, et al: IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 11:1093–1101. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Zeng JC, Zhang Z, Li TY, Liang YF, Wang HM, Bao JJ, Zhang JA, Wang WD, Xiang WY, Kong B, et al: Assessing the role of IL-35 in colorectal cancer progression and prognosis. Int J Clin Exp Pathol. 6:1806–1816. 2013.PubMed/NCBI

8 

Jin P, Ren H, Sun W, Xin W, Zhang H and Hao J: Circulating IL-35 in pancreatic ductal adenocarcinoma patients. Hum Immunol. 75:29–33. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Jin L, Xu X, Ye B, Pan M, Shi Z and Hu Y: Elevated serum interleukin-35 levels correlate with poor prognosis in patients with clear cell renal cell carcinoma. Int J Clin Exp Med. 8:18861–18866. 2015.PubMed/NCBI

10 

Wu W, Jiang H, Li Yi and Yan MX: IL-35 expression is increased in laryngeal squamous cell carcinoma and in the peripheral blood of patients. Oncol Lett. 13:3303–3308. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Wang Z, Liu JQ, Liu Z, Shen R, Zhang G, Xu J, Basu S, Feng Y and Bai X: Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J Immunol. 190:2415–2423. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Nicholl MB, Ledgewood CL, Chen XH, Bai Q, Qin CL, Cook KM, Herrick EJ, DiazArias A, Moore BJ and Fang YJ: IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: Evidence for a role as an autocrine growth factor. Cytokine. 70:126–133. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Zhao Z, Chen X, Hao SN, Jia R, Wang N, Chen S, Li M, Wang C and Mao H: Increased interleukin-35 expression in tumor-infiltrating lymphocytes correlates with poor prognosis in patients with breast cancer. Cytokine. 89:76–81. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Tao Q, Pan Y, Wang Y, Wang H, Xiong S, Li Q, Wang J, Tao L, Wang Z, Wu F, et al: Regulatory T cells derived IL-35 promotes the growth of adult acute myeloid leukemia blasts. Int J Cancer. 137:2384–2393. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Gu X, Tian T, Zhang B, Liu Y, Yuan C, Shao LJ, Guo Y and Fan K: Elevated plasma interleukin-35 levels predict poor prognosis in patients with non-small cell lung cancer. Tumour Biol. 36:2651–2656. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Fu YP, Yi Y, Cai XY, Sun J, Ni XC, He HW, Wang JX, Lu ZF, Huang JL, Cao Y, et al: Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 114:767–776. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Fan YG, Zhai JM, Wang W, Feng B, Yao GL, An YH and Zeng Chao: IL-35 over-expression is associated with genesis of gastric cancer. Asian Pac J Cancer Prev. 16:2845–2849. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Buyyounouski MK, Choyke PL, McKenney JK, Sartor O, Sandler HM, Amin MB, Kattan MW and Lin DW: Prostate cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 67:245–253. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR and Humphrey PA; Grading Committee, : The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of prostatic carcinoma: Definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 40:244–252. 2016.PubMed/NCBI

20 

Whiteside TL: The tumor microenvironment and its role in promoting tumor growth. Oncogene. 27:5904–5912. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Salomon BL, Leclerc M, Tosello J, Ronin E, Piaggio E and Cohen JL: Tumor necrosis factor α and regulatory T cells in oncoimmunology. Front Immunol. 9:4442018. View Article : Google Scholar : PubMed/NCBI

22 

Vivekanandhan S and Mukhopadhyay D: Genetic status of KRAS influences transforming growth factor-beta (TGF-β) signaling: An insight into Neuropilin-1 (NRP1) mediated tumorigenesis. Semin Cancer Biol. 54:72–79. 2019. View Article : Google Scholar : PubMed/NCBI

23 

Huang S, Liu Q, Liao Q, Wu Q, Sun B, Yang Z, Hu X, Tan M and Li L: Interleukin-6/signal transducer and activator of transcription 3 promotes prostate cancer resistance to androgen deprivation therapy via regulating pituitary tumor transforming gene 1 expression. Cancer Sci. 109:678–687. 2018. View Article : Google Scholar : PubMed/NCBI

24 

Seyerl M, Kirchberger S, Majdic O, Seipelt J, Jindra C, Schrauf C and Stöckl J: Human rhinoviruses induce IL-35-producing Treg via induction of B7-H1 (CD274) and sialo adhesin (CD169) on DC. Eur J Immunol. 40:321–329. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Zhou C, Zhang J, Chen Y, Wang H and Hou J: Interleukin-35 as a predictor of prostate cancer in patients undergoing initial prostate biopsy. Onco Targets Ther. 10:3485–3491. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Chatrabnous N, Ghaderi A, Ariafar A, Razeghinia M S, Nemati M and Jafarzadeh A: Serum concentration of interleukin-35 and its association with tumor stages and FOXP3 gene polymorphism in patients with prostate cancer. Cytokine. 113:221–227. 2019. View Article : Google Scholar : PubMed/NCBI

27 

Zhang Y, Sun H, Wu H, Tan QD and Xiang K: Interleukin 35 is an independent prognostic factor and a therapeutic target for nasopharyngeal carcinoma. Contemp Oncol (Pozn). 2:120–124. 2015.

28 

Huang C, Li N, Li Z, Chang A, Chen Y, Zhao T, Li Y, Wang X, Zhang W, Wang Z, et al: Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression. Nat Commun. 8:140352017. View Article : Google Scholar : PubMed/NCBI

29 

Huang C, Li Z, Li N, Li Y, Chang A, Zhao T, Wang X, Wang H, Gao S, Yang S, et al: Interleukin 35 expression correlates with microvessel density in pancreatic ductal adenocarcinoma, recruits monocytes, and promotes growth and angiogenesis of Xenograft tumors in mice. Gastroenterology. 154:675–688. 2018. View Article : Google Scholar : PubMed/NCBI

30 

Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM, Yano H, Beres AJ, Vogel P, Workman CJ and Vignali DA: Interleukin-35 limits anti-tumor immunity. Immunity. 44:316–329. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Wang K, Liu J and Li J: IL-35-producing B cells in gastric cancer patients. Medicine (Baltimore). 97:e07102018. View Article : Google Scholar : PubMed/NCBI

33 

Trinchieri G, Pflanz S and Kastelein RA: The IL-12 family of heterodimeric cytokines: New players in the regulation of T cell responses. Immunity. 19:641–644. 2003. View Article : Google Scholar : PubMed/NCBI

34 

Sun L, He C, Nair L, Yeung J and Egwuagu CE: Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine. 75:249–255. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, et al: The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 13:290–299. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, Wingfeld PT, Kim SH and Egwuagu CE: Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 20:633–641. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Ma YH, Chen L, Xie G, Zhou Y, Yue C, Yuan X, Zheng Y, Wang W, Deng L and Shen L: Elevated level of Interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3. Oncotarget. 7:73003–73015. 2016. View Article : Google Scholar : PubMed/NCBI

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June 2019
Volume 17 Issue 6

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Copy and paste a formatted citation
APA
Zhu, J., Yang, X., Wang, Y., Zhang, H., & Guo, Z. (2019). Interleukin‑35 is associated with the tumorigenesis and progression of prostate cancer. Oncology Letters, 17, 5094-5102. https://doi.org/10.3892/ol.2019.10208
MLA
Zhu, J., Yang, X., Wang, Y., Zhang, H., Guo, Z."Interleukin‑35 is associated with the tumorigenesis and progression of prostate cancer". Oncology Letters 17.6 (2019): 5094-5102.
Chicago
Zhu, J., Yang, X., Wang, Y., Zhang, H., Guo, Z."Interleukin‑35 is associated with the tumorigenesis and progression of prostate cancer". Oncology Letters 17, no. 6 (2019): 5094-5102. https://doi.org/10.3892/ol.2019.10208