Top

Published in:

01-04-2014 | Research Article

Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis

Authors: Ying Liu, Su-jun Gao, Bo-xiang Du, Jie-jun Wang

Published in: Tumor Biology | Issue 4/2014

Abstract

The associations between IL-6 gene single nucleotide polymorphisms (SNPs) and risk of hepatocellular carcinoma (HCC) are controversial. We performed a meta-analysis to provide more credible evidence. We searched for relevant studies published up to 2013 by performing an efficient searching strategy. Odds ratios (OR) with 95 % confidence interval (95 % CI) was used to estimate the strength of the associations between IL-6 polymorphisms and HCC risk. We identified eight case–control studies involving 1,448 HCC cases and 3,160 controls. Our estimation specifically focused on two SNPs of the IL-6 gene, −174 G/C and −572 G/C. The combined results showed that association between IL-6-174 G/C polymorphism and risk of HCC was significant under additive model (CC vs. GG: OR 0.36; 95 % CI, 0.16, 0.85) and recessive model (GG+CG vs. CC: OR 2.82; 95 % CI 1.26, 6.28). However, the IL-6-572 G/C polymorphism was not associated with HCC risk. In conclusion, IL-6-174 G/C, but not −572 G/C polymorphism could be a candidate for susceptibility to HCC. However, the results should be cautiously interpreted due to the limited number of the included studies.

El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.PubMedCrossRef

Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–17.PubMedCrossRef

Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5–S16.PubMedCrossRef

Parikh S, Hyman D. Hepatocellular cancer: a guide for the internist. Am J Med. 2007;120(3):194–202.PubMedCrossRef

Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.PubMedCrossRef

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.PubMedCentralPubMedCrossRef

Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res. 2011;185:135–48.PubMedCrossRef

Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25(27):3834–47.PubMedCrossRef

Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 2007;46(2):590–7.PubMedCrossRef

10.

Oyanagi Y, Takahashi T, Matsui S, Takahashi S, Boku S, Takahashi K, et al. Enhanced expression of interleukin-6 in chronic hepatitis C. Liver. 1999;19(6):464–72.PubMedCrossRef

11.

Naugler WE, Karin M. The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14(3):109–19.PubMedCrossRef

12.

Soresi M, Giannitrapani L, D'Antona F, Florena AM, La Spada E, Terranova A, et al. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma. World J Gastroenterol. 2006;12(16):2563–8.PubMed

13.

Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, et al. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Annals Oncol. 2008;19(2):353–8.CrossRef

14.

Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, et al. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer. 2009;124(12):2766–70.PubMedCrossRef

15.

Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol. 1998;16(3–4):249–84.PubMedCrossRef

16.

Basso D, Scrigner M, Toma A, Navaglia F, Di Mario F, Rugge M, et al. Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res. 1996;26(3):207–10.PubMedCrossRef

17.

Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275(24):18138–44.PubMedCrossRef

18.

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–76.PubMedCentralPubMedCrossRef

19.

Hefler LA, Grimm C, Ackermann S, Malur S, Radjabi-Rahat AR, Leodolter S, et al. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res. 2003;63(12):3066–8.PubMed

20.

Olomolaiye O, Wood NA, Bidwell JL. A novel NlaIII polymorphism in the human IL-6 promoter. Eur J Immunogenet. 1998;25(2–3):267.PubMedCrossRef

21.

Yang Z, Liang Y, Qin B, Zhong R. A meta-analysis of the association of IL-6-174 G/C and -572 G/C polymorphisms with systemic lupus erythematosus risk. Rheumatol Int. 2013, doi:10.1007/s00296-013-2855-4.

22.

Yang Y, Zhang F, Skrip L, Lei H, Wang Y, Hu D, et al. IL-6 gene polymorphisms and CAD risk: a meta-analysis. Mol Biol Rep. 2013;40(3):2589–98.PubMedCrossRef

23.

Sfrent-Cornateanu R, Mihai C, Balan S, Ionescu R, Moldoveanu E. The IL-6 promoter polymorphism is associated with disease activity and disability in systemic sclerosis. J Cell Mol Med. 2006;10(4):955–9.PubMedCrossRef

24.

Belluco C, Olivieri F, Bonafe M, Giovagnetti S, Mammano E, Scalerta R, et al. 174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res. 2003;9(6):2173–6.PubMed

25.

Qi L, van Dam RM, Meigs JB, Manson JE, Hunter D, Hu FB. Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case–control study and meta-analysis. Hum Mol Genet. 2006;15(11):1914–20.PubMedCrossRef

26.

Jiang RQ, Deng L, Zhao L, Li XC, Zhang F, Xia YX, et al. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res. 2011;17(17):5593–603.PubMedCrossRef

27.

Jain S, Li Y, Patil S, Kumar A. A single-nucleotide polymorphism in human angiotensinogen gene is associated with essential hypertension and affects glucocorticoid induced promoter activity. J Mol Med (Berl). 2005;83(2):121–31.CrossRef

28.

Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem. 1993;268(15):10739–45.PubMed

29.

Cussigh A, Falleti E, Fabris C, Bitetto D, Cmet S, Fontanini E, et al. Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C. Immunogenetics. 2011;63(1):33–41.PubMedCrossRef

30.

Minton EJ, Smillie D, Smith P, Shipley S, McKendrick MW, Gleeson DC, et al. Clearance of hepatitis C virus is not associated with single nucleotide polymorphisms in the IL-1,-6, or-10 genes. Hum Immunol. 2005;66(2):127–32.PubMedCrossRef

31.

Falleti E, Fabris C, Vandelli C, Colletta C, Cussigh A, Smirne C, et al. Genetic polymorphisms of interleukin-6 modulate fibrosis progression in mild chronic hepatitis C. Hum Immunol. 2010;71(10):999–1004.PubMedCrossRef

32.

Saxena R, Chawla YK, Kaur J. Association of IL-6 gene polymorphism and its levels in HBV related hepatocellular carcinoma progression in India. Int J Infect Dis. 2011;15:S75–6.CrossRef

33.

Giannitrapani L, Soresi M, Giacalone A, Campagna ME, Marasa M, Cervello M, et al. IL-6–174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma. OMICS. 2011;15(3):183–6.PubMedCrossRef

34.

Ognjanovic S, Yuan JM, Chaptman AK, Fan Y, Yu MC. Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA. Carcinogenesis. 2009;30(5):758–62.PubMedCentralPubMedCrossRef

35.

Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Bitetto D, et al. Interleukin-6 polymorphisms and gender: relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology. 2009;77(5):304–13.PubMedCrossRef

36.

Migita K, Miyazoe S, Maeda Y, Daikoku M, Abiru S, Ueki T, et al. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-beta1 polymorphisms and hepatocellular carcinoma. J Hepatol. 2005;42(4):505–10.PubMedCrossRef

37.

Ben-Ari Z, Mor E, Papo O, Kfir B, Sulkes J, Tambur AR, et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol. 2003;98(1):144–50.PubMedCrossRef

38.

Liu S, Qiu XQ, Zeng XY, Bai H, Bei CH, Yang Y. Relationship between IL6-572G/C polymorphism and hepatocellular carcinoma in men. Zhonghua Gan Zang Bing Za Zhi. 2012;20(6):463–7.PubMed

39.

Qiu XQ, Bei CH, Yu HP, Zeng XY, Zhong QA. Study on the relationship between single-nucleotide polymorphisms in IL-6, IL-10 genes and HBV-related hepatocellular carcinoma. Zhonghua Liu Xing Bing Xue Za Zhi. 2011;32(5):510–3.PubMed

40.

Park BL, Lee HS, Kim YJ, Kim JY, Jung JH, Kim LH, et al. Association between interleukin 6 promoter variants and chronic hepatitis B progression. Exp Mol Med. 2003;35(2):76–82.PubMedCrossRef

41.

Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green F, et al. Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem. 2004;50(11):2136–40.PubMedCrossRef

42.

Cox ED, Hoffmann SC, DiMercurio BS, Wesley RA, Harlan DM, Kirk AD, et al. Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6. Transplantation. 2001;72(4):720–6.PubMedCrossRef

43.

Jerrard-Dunne P, Sitzer M, Risley P, Buehler A, von Kegler S, Markus HS. Inflammatory gene load is associated with enhanced inflammation and early carotid atherosclerosis in smokers. Stroke. 2004;35(11):2438–44.PubMedCrossRef

44.

Xu B, Niu XB, Wang ZD, Cheng W, Tong N, Mi YY, et al. IL-6–174G>C polymorphism and cancer risk: a meta-analysis involving 29,377 cases and 37,739 controls. Mol Biol Rep. 2011;38(4):2589–96.PubMedCrossRef

45.

Wang J, He W, Liu J, Nong L, Wei Y, Yang F. Association of IL-6 polymorphisms with gastric cancer risk: evidences from a meta-analysis. Cytokine. 2012;59(1):176–83.PubMedCrossRef

46.

Yin YW, Sun QQ, Hu AM, Wang Q, Liu HL, Hou ZZ, et al. Associations between interleukin‐6 gene −174 C/G and −572 C/G polymorphisms and the risk of gastric cancer: a meta-analysis. J Surg Oncol. 2012;106(8):987–93.PubMedCrossRef

Title: Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis
Authors: Ying Liu
Su-jun Gao
Bo-xiang Du
Jie-jun Wang
Publication date: 01-04-2014
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 4/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-013-1469-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2014

FokI polymorphism in vitamin D receptor gene and risk of breast cancer among Caucasian women

Differential expression profiling of microRNAs and their potential involvement in esophageal squamous cell carcinoma

N-acetyltransferase 2 genetic variants confer the susceptibility to head and neck carcinoma: evidence from 23 case–control studies

Tetra-arsenic tetra-sulfide (As4S4) promotes apoptosis in retinoid acid -resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein

The association between cytotoxic T lymphocyte-associated antigen-4 and cervical cancer

Association between cytotoxic T lymphocyte antigen-4 +49A/G, −1722T/C, and −1661A/G polymorphisms and cancer risk: a meta-analysis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer