Abstract
Lung cancer was found to be the most commonly diagnosed cancer, as well as the primary cause of cancer-related mortality for males worldwide and the second leading cause of cancer-related deaths for women. Cytokines are fundamental for several biological processes-associated malignant tumors. The IL-6 is a cytokine involved in the regulation of cellular functions including processes associated with cancer, such as proliferation, apoptosis, angiogenesis, and differentiation. Furthermore, IL-6 is a potent pleiotropic inflammatory cytokine that is considered a key growth-promoting and antiapoptotic factor. The polymorphism − 174G/C SNP is a G to C transition in the -174 position of the promoter region of the IL-6 gene. The aim of our study was to evaluate the influence of -174G/C polymorphism in clinical outcome of non-small cell cancer (NSCLC) patients. DNA was extracted from peripheral blood of 424 patients diagnosed with cytologically or histologically NSCLC. The characterization of IL-6 -174G/C genotypes was performed by PCR-RFLP (NlaIII). IL-6 polymorphism’s genotypes were divided according to functional activity, so the G carriers (CG/GG) is the high-producer IL-6, and CC genotype is the low-producer IL-6. Regarding survival, we verify that patients with genotypes carrying the G allele (CG/GG) had a statistically significant diminished survival when compared with patients with CC genotype (62.79 and 42.31 months, respectively; P = 0.032). In the promoter region of the IL-6 gene, polymorphic variants were located and may be responsible for alterations in transcription that consequently affect serum levels of the cytokine. With our study, we demonstrated that genetic variant (-174G/G and G/C) can be responsible for changes in prognosis of NSCLC patients.

References
Jemal A et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.
Molina JR et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94.
Araujo A et al. Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer—a review of the literature. Oncologist. 2007;12(2):201–10.
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.
Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117(5):1175–83.
Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15(2):425–30.
Brandao GD, Brega EF, Spatz A. The role of molecular pathology in non-small-cell lung carcinoma-now and in the future. Curr Oncol. 2012;19 Suppl 1:S24–32.
Crohns M et al. Cytokines in bronchoalveolar lavage fluid and serum of lung cancer patients during radiotherapy—association of interleukin-8 and VEGF with survival. Cytokine. 2010;50(1):30–6.
Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46(7):1223–31.
Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 2002;4 Suppl 3:S233–42.
Lukaszewicz M, Mroczko B, Szmitkowski M. Clinical significance of interleukin-6 (IL-6) as a prognostic factor of cancer disease. Pol Arch Med Wewn. 2007;117(5-6):247–51.
Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol. 2001;159(6):2159–65.
Culig Z et al. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95(3):497–505.
Giannitrapani L et al. Genetic association of interleukin-6 polymorphism (-174G/C) with chronic liver diseases and hepatocellular carcinoma. World J Gastroenterol. 2013;19(16):2449–55.
Hefler LA et al. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res. 2003;63(12):3066–8.
Zhang X et al. IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line. Anticancer Res. 2009;29(11):4497–501.
Zarogoulidis P et al. Interleukin-6 cytokine: a multifunctional glycoprotein for cancer. Immunol Res. 2013;9(62):16535.
Liu RY et al. Association between IL6–174G/C and cancer: a meta-analysis of 105,482 individuals. Exp Ther Med. 2012;3(4):655–64.
Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 2002;13(4–5):357–68.
Pine SR et al. Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. J Natl Cancer Inst. 2011;103(14):1112–22.
Azevedo A et al. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011;2(12):384–96.
De Vita F et al. Serum concentrations of proinflammatory cytokines in advanced non small cell lung cancer patients. J Exp Clin Cancer Res. 1998;17(4):413–7.
Olomolaiye O, Wood NA, Bidwell JL. A novel NlaIII polymorphism in the human IL-6 promoter. Eur J Immunogenet. 1998;25(2–3):267.
Fishman D 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 Investig. 1998;102(7):1369–76.
Mandal S, Abebe F, Chaudhary J. 174G/C polymorphism in the interleukin-6 promoter is differently associated with prostate cancer incidence depending on race. Genet Mol Res. 2014;13(1):139–51.
Cox ED et al. Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6. Transplantation. 2001;72(4):720–6.
Meenagh A et al. Frequency of cytokine polymorphisms in populations from Western Europe, Africa, Asia, the Middle East and South America. Hum Immunol. 2002;63(11):1055–61.
Oken MM et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55.
Husten CG. How should we define light or intermittent smoking? Does it matter? Nicotine Tob Res. 2009;11(2):111–21.
Kristiansen OP et al. Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females. Hum Mol Genet. 2003;12(10):1101–10.
Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121(11):2373–80.
Yang M, Li C, Li M. Association of interleukin-6 (-174G/C) polymorphism with the prostate cancer risk: a meta-analysis. Biomed Rep. 2014;2(5):637–43.
Zhou B et al. C-reactive protein, interleukin 6 and lung cancer risk: a meta-analysis. PLoS ONE. 2012;7(8):e43075.
Wojcik E et al. IL-6 and VEGF in small cell lung cancer patients. Anticancer Res. 2010;30(5):1773–8.
Ara T et al. Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 2009;69(1):329–37.
Ogata A et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol. 1997;159(5):2212–21.
Smith PC et al. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev. 2001;12(1):33–40.
Bollrath J et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15(2):91–102.
Niu G et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 2002;21(46):7001–10.
Quintanilla-Martinez L et al. Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events. Am J Pathol. 2003;162(5):1449–61.
Gao SP et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117(12):3846–56.
Kim MY et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139(7):1315–26.
Song XY et al. Research on the relationship between serum levels of inflammatory cytokines and non-small cell lung cancer. Asian Pac J Cancer Prev. 2013;14(8):4765–8.
Markkula A et al. IL6 genotype, tumour ER-status, and treatment predicted disease-free survival in a prospective breast cancer cohort. BMC Cancer. 2014;14:759.
Tan D et al. Interleukin-6 polymorphism is associated with more aggressive prostate cancer. J Urol. 2005;174(2):753–6.
Talar-Wojnarowska R et al. Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci. 2009;54(3):683–9.
Garg R et al. Common polymorphism in interleukin 6 influences survival of women with ovarian and peritoneal carcinoma. Gynecol Oncol. 2006;103(3):793–6.
Wang YS et al. Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with clinical outcome of erlotinib treatment. Chin Med J (Engl). 2013;126(20):3931–5.
Enewold L et al. Serum concentrations of cytokines and lung cancer survival in African Americans and Caucasians. Cancer Epidemiol Biomarkers Prev. 2009;18(1):215–22.
Chang CH et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer. 2013;132(9):1977–85.
DeMichele A et al. Interleukin-6–174G– > C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res. 2003;63(22):8051–6.
Patel SA et al. Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. Br J Cancer. 2014;111(12):2287–96.
Acknowledgments
We thank the Liga Portuguesa Contra o Cancro-Centro Regional do Norte (Portuguese League Against Cancer) for their support.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gomes, M., Coelho, A., Araújo, A. et al. IL-6 polymorphism in non-small cell lung cancer: a prognostic value?. Tumor Biol. 36, 3679–3684 (2015). https://doi.org/10.1007/s13277-014-3006-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-3006-6