Skip to main content

Advertisement

SpringerLink
Log in

Plasma Level of Interleukin-35 as an Independent Prognostic Indicator in Hepatocellular Carcinoma

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Hepatocellular carcinoma is a major type of liver cancer with poor prognosis.

Aim

The aim of the study was to determine the prognostic significance of plasma interleukin-35 level in hepatocellular carcinoma.

Methods

A total of 153 hepatocellular carcinoma patients and 153 healthy controls were enrolled. Blood samples were obtained at admission. Plasma interleukin-35 level was analyzed by enzyme-linked immunosorbent assay. Distribution of T cell subset and expression of Fas/FasL protein were detected by flow cytometry. The patients were followed up for 2 years. Poor prognosis was defined as death of hepatocellular carcinoma.

Results

The plasma levels of interleukin-35 were significantly higher in the patients than the controls (25.1 ± 13.1, 9.3 ± 6.3 pg/mL, P < 0.001). After adjusted for multiple confounding factors, the multivariate logistic regression analyses reported that high level of interleukin-35 (≥25.0 pg/mL) was associated with the poor prognosis in the patients (OR 6.63, 95 % CI 3.27–13.47). Compared with the patients with low level of interleukin-35 (<25.0 pg/mL), the patients with high level of interleukin-35 showed higher frequencies of CD4+CD25+FoxP3+ and CD3+Foxp3+ regulatory T cells (P < 0.001 and P < 0.001) and also showed higher apoptosis levels of CD8+ T cells (P < 0.001).

Conclusion

Circulating interleukin-35 concentration might be an independent prognostic indicator in hepatocellular carcinoma. Such prognostic significance could be partly involved in the activation of regulatory T cell and the apoptosis of CD8+ T cell.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Grewal P, Viswanathen VA. Liver cancer and alcohol. Clin Liver Dis. 2012;16:839–850.

    Article  PubMed  Google Scholar 

  2. Li DK, Chung RT. Impact of hepatitis C virus eradication on hepatocellular carcinogenesis. Cancer. 2015;121:2874–2882.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lai H, Mo X, Yang Y, et al. Association between aflatoxin B1 occupational airway exposure and risk of hepatocellular carcinoma: a case-control study. Tumour Biol. 2014;35:9577–9584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang TS, Wu YC, Tung SY, et al. Alpha-fetoprotein measurement benefits hepatocellular carcinoma surveillance in patients with cirrhosis. Am J Gastroenterol. 2015;110:836–844.

    Article  CAS  PubMed  Google Scholar 

  5. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–1359.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Inokawa Y, Sugimoto H, Kanda M, et al. Hepatectomy for hepatocellular carcinoma in patients with hemophilia. J Hepatobiliary Pancreat Sci. 2014;21:824–828.

    Article  PubMed  Google Scholar 

  7. Singh P, Kaur H, Lerner RG, Patel R, Rafiyath SM, Singh Lamba G. Hepatocellular carcinoma in non-cirrhotic liver without evidence of iron overload in a patient with primary hemochromatosis. Rev J Gastrointest Cancer. 2012;43:36–39.

    Article  Google Scholar 

  8. Cheng WS, Govindarajan S, Redeker AG. Hepatocellular carcinoma in a case of Wilson’s disease. Liver. 1992;12:42–45.

    Article  CAS  PubMed  Google Scholar 

  9. Fan J, Yang GS, Fu ZR, et al. Liver transplantation outcomes in 1,078 hepatocellular carcinoma patients: a multi-center experience in Shanghai,China. J Cancer Res Clin Oncol. 2009;135:1403–1412.

    Article  PubMed  Google Scholar 

  10. Park JG. Long-term outcomes of patients with advanced hepatocellular carcinoma who achieved complete remission after sorafenib therapy. Clin Mol Hepatol. 2015;21:287–294.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tanabe KK, Curley SA, Dodd GD, Siperstein AE, Goldberg SN. Radiofrequency ablation: the experts weigh in. Cancer. 2004;100:641–650.

    Article  PubMed  Google Scholar 

  12. Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review. Eur J Cancer. 2004;40:1474–1484.

    Article  CAS  PubMed  Google Scholar 

  13. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  14. Devergne O, Birkenbach M, Kieff E. Epstein–Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc Natl Acad Sci USA. 1997;94:12041–12046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–569.

    Article  CAS  PubMed  Google Scholar 

  16. Wirtz S, Billmeier U, Mchedlidze T, Blumberg RS, Neurath MF. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology. 2011;141:1875–1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA. Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol. 2011;186:6661–6666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11:1093–1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lu Y, Yuan Y. Serum level of interleukin-17 and interleukin-35 as a biomarker for diagnosis of thyroid cancer. J Cancer Res Ther. 2015;11:209–211.

    Article  Google Scholar 

  20. Zhang Y, Sun H, Wu H, Tan Q, Xiang K. Interleukin 35 is an independent prognostic factor and a therapeutic target for nasopharyngeal carcinoma. Contemp Oncol (Pozn). 2015;19:120–124.

    CAS  Google Scholar 

  21. Zeng JC, Zhang Z, Li TY, et al. Assessing the role of IL-35 in colorectal cancer progression and prognosis. Int J Clin Exp Pathol. 2013;6:1806–1816.

    PubMed  PubMed Central  Google Scholar 

  22. Gu X, Tian T, Zhang B, et al. Elevated plasma interleukin-35 levels predict poor prognosis in patients with non-small cell lung cancer. Tumour Biol. 2015;36:2651–2656.

    Article  CAS  PubMed  Google Scholar 

  23. Fu YP, Yi Y, Cai XY, et al. Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 2016;114:767–776.

    Article  CAS  PubMed  Google Scholar 

  24. Ferenci P, Fried M, Labrecque D, et al. World Gastroenterology Organisation Guideline. Hepatocellular carcinoma (HCC): a global perspective. J Gastrointest Liver Dis. 2010;19:311–317.

    Google Scholar 

  25. 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;17:1471–1474.

    Article  PubMed  Google Scholar 

  26. Fu YP, Yi Y, Cai XY, et al. Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 2016;114:767–776.

    Article  CAS  PubMed  Google Scholar 

  27. Chen Y, Wang CJ, Lin SH, Zhang M, Li SY, Xu F. Interleukin-35 is upregulated in response to influenza virus infection and secondary bacterial pneumonia. Cytokine. 2016;81:23–27.

    Article  CAS  PubMed  Google Scholar 

  28. Shibolet O, Alper R, Zlotogarov L, et al. NKT and CD8 lymphocytes mediate suppression of hepatocellular carcinoma growth via tumor antigen-pulsed dendritic cells. Int J Cancer. 2003;106:236–243.

    Article  CAS  PubMed  Google Scholar 

  29. Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328–2339.

    Article  PubMed  Google Scholar 

  30. Shi YY, Dai MJ, Wu GP, Zhou PP, Fang Y, Yan XB. Levels of interleukin-35 and its relationship with regulatory T-cells in chronic hepatitis B patients. Viral Immunol. 2015;28:93–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guo CL, Yang XH, Cheng W, et al. Expression of Fas/FasL in CD8+ T and CD3+ Foxp3+ Treg cells–relationship with apoptosis of circulating CD8+ T cells in hepatocellular carcinoma patients. Asian Pac J Cancer Prev. 2014;15:2613–2618.

    Article  PubMed  Google Scholar 

  32. Long J, Zhang X, Wen M, et al. IL-35 over-expression increases apoptosis sensitivity and suppresses cell growth in human cancer cells. Biochem Biophys Res Commun. 2013;430:364–369.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Yishui Central Hospital, No. 17, Health Road, Yishui County, Linyi, 276400, Shandong, China

    Xiangting Qiu, Xinhua Wang, Yucui Song & Lingling Chen

Authors
  1. Xiangting Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinhua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yucui Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lingling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lingling Chen.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiu, X., Wang, X., Song, Y. et al. Plasma Level of Interleukin-35 as an Independent Prognostic Indicator in Hepatocellular Carcinoma. Dig Dis Sci 61, 3513–3521 (2016). https://doi.org/10.1007/s10620-016-4270-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-016-4270-7

Keywords

Search

Navigation