Abstract
Chemokines are small inducible pro-inflammatory cytokines. In the present study, we tested association of chemokine single nucleotide polymorphisms (SNPs) viz., CCR5∆32, CXCL12G801A and CXCR2C1208T genes in bladder cancer (BC) patients and normal healthy controls of north Indians. Genotyping of the above SNPs were done in 200 BC cases and 200 healthy controls, using RFLP and amplification refractory mutation system–polymerase chain reaction methodology. A significant association was found in CXCL12G801A with BC risk. In case of CXCL12G801A polymorphism, the heterozygous (GA) genotype showed significantly high risk (p < 0.001, odds ratio (OR) = 2.72), whereas A allele carrier (GA + AA) also showed risk with BC (p < 0.001, OR = 2.44). In CXCR2C1208T polymorphism, the variant genotype (TT) showed significant risk for BC (p = 0.028, OR = 1.58). The variant allele (T) of CXCR2C1208T polymorphism was found to be associated with BC risk (p = 0.003, OR = 1.29). Interestingly, smoking was also found to modulate 1.16-fold risks for BC in case of CXCR2C1208T, variant genotype (TT). Upon analyzing the gene–gene interaction between CXCR2C1208T and CXCL12G801A, the combination CT-GA showed 4-fold risk for BC (p = 0.009). Our results indicated that polymorphism in CXCR2C1208T and CXCL12G801A showed high risk for BC in north Indian population. However, CCR5∆32 exhibited no association. Study with large sample size and diverse ethnicity are required to validate these observations.
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Raman D, Baugher PJ, Thu YM, et al. Role of chemokines in tumor growth. Cancer Lett. 2007;256:137–65.
Morgan D, Mahe C, Mayanja B, et al. Progression to symptomatic disease in people infected with HIV-1 in rural Uganda: prospective cohort study. BMJ. 2002;324:193–6.
Horuk R. Molecular properties of the chemokines receptor family. Trends Pharmacol Sci. 1994;15:159–65.
Ruster M, Sperschneider H, Funfstuck R, Stein G, Grone HJ. Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol. 2004;61:30–9.
Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367–77.
Huang Y, Paxton WA, Wolinsky SM, et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996;2:1240–3.
Borish LC, Steinke JW. Cytokines and chemokines. J Allergy Clin Immunol. 2003;111:S460–75.
Apostolakis S, Baritaki S, Kochiadakis GE, et al. Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease. Thromb Res. 2007;119:63–71.
Hirata H, Hinoda Y, Kikuno N, et al. CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin Cancer Res. 2007;13:5056–62.
de Oliveira CE, Cavassin GG, Perim Ade L, et al. Stromal cell-derived factor-1 chemokine gene variant in blood donors and chronic myelogenous leukemia patients. J Clin Lab Anal. 2007;21:49–54.
Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50.
Brant E, Ludwig A, Petersen F, Flad HD. Platelet-derived CXC chemokines: old players in new games. Immunol Rev. 2000;177:204–16.
Renzoni E, Lympany P, Sestini P. Distribution of novel polymorphisms of IL-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633–40.
Colombel M, Soloway M, Akaza H. Epidemiology, staging, grading and risk stratification of bladder cancer. Eur Urol. 2008;7:618–26.
Miller SA, Dykes DD, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
Singh R, Kapoor R, Srivastava A, et al. Impact of chemokine receptor CCR2 and CCR5 gene polymorphism on allograft outcome in north Indian renal transplant recipients. Scand J Immunol. 2009;69:51–6.
Manchanda PK, Singh R, Mittal RD. Cytokine (IL-10–1082 and -819) and chemokine receptor (CCR2 and CCR5) gene polymorphism in north Indian patients with end-stage renal disease. DNA Cell Biol. 2009;28:177–83.
Ahluwalia TS, Khullar M, Ahuja M, et al. Common variants of inflammatory cytokine genes are associated with risk of nephropathy intype 2 diabetes among Asian Indians. PLoS One. 2009;4:51–68.
D’Angelo R, Crisafulli C, Rinaldi C, et al. CCR5Δ32 polymorphism associated with a slower rate disease progression in a cohort of RR-MS Sicilian patients. Mult Scler Int. 2011;2011:153–82.
Srivastava A, Pandey SN, Choudhuri G, et al. CCR5 Delta32 polymorphism associated with gallbladder cancer susceptibility. Scand J Immunol. 2008;67:516–22.
Kucukgergin C, Isman FK, Dasdemir S, et al. The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer. Gene. 2012;10(511):7–11.
Zafiropoulos A, Crikas N, Passam AM, Spandidos DA. Significant involvement of CCR2–64I and CXCL12–3a in the development of sporadic breast cancer. J Med Genet. 2004;41:e59.
Paterlini MG. Structure modeling of the chemokine receptor CCR5: implications for ligand binding and selectivity. Biophys J. 2002;83:3012–31.
Kruszyna L, Lianeri M, Rubis B, et al. CCL2–2518 A/G single nucleotide polymorphism as a risk factor for breast cancer. Mol Biol Rep. 2010;38:1263–7.
Teng YH, Liu TH, Tseng HC, et al. Contribution of genetic polymorphisms of stromal cell-derived factor-1and its receptor, CXCR4, to the susceptibility and clinicopathologic development of oral cancer. Head Neck. 2009;31:1282–8.
Dimberg J, Hugander A, Löfgren S, et al. Polymorphism and circulatinglevels of the chemokine CXCL12 in colorectal cancer patients. Int J Mol Med. 2007;1:11–5.
Ku FC, Tsai CR, Der Wang J, et al. Stromal-derived factor-1 gene variations in pediatric patients with primary immune thrombocytopenia. Eur J Haematol. 2013;90:25–30.
Vairaktaris E, Vylliotis A, Spyridonodou S, et al. DNA polymorphism of stromal-derived factor-1 is associated with advanced stages of oral cancer. Anticancer Res. 2008;28:271–5.
Lian LH, Kee BP, Ng HL, et al. Lack of association between RANTES-28, SDF-1 gene polymorphisms and systemic lupus erythematosus in the Malaysian population. Genet Mol Res. 2011;10:2841–50.
Işman FK, Kucukgergin C, Daşdemir S, et al. Association between SDF1-3′A or CXCR4 gene polymorphisms with predisposition toand clinicopathological characteristics of prostate cancer with or without metastases. Mol Biol Rep. 2012;39:1073–9.
Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C, et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann Surg. 2006;244:113–20.
Crazzolara R, Kreczy A, Mann G, et al. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol. 2001;115:545–53.
Javor J, Bucova M, Cervenova O, et al. Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acutepyelonephritis in children. Int J Immunogenet. 2012;39:338–45.
Duymaz-Tozkir J, Yilmaz V, Uyar FA, et al. Polymorphisms of the IL-8 and CXCR2 genes are not associated with Behçet’s disease. J Rheumatol. 2005;32:93–7.
Snoussi K, Mahfoudh W, Bouaouina N, et al. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer. 2010;12:10–283.
Salim PH, Jobim M, Bredemeier M, et al. Combined effects of CXCL8 and CXCR2 gene polymorphisms on susceptibility to systemic sclerosis. Cytokine. 2012;60:473–7.
Ben-Baruch A. Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res. 2003;5:31–6.
Acknowledgments
We are thankful to the urologists in our department for providing bladder cancer samples and relevant clinical information of patients. Vibha Singh is thankful to ICMR New Delhi for providing Senior Research Fellowship (SRF) and Praveen Kumar Jaiswal is thankful to UGC New Delhi for providing Junior Research Fellowship (JRF).
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Singh, V., Jaiswal, P.K., Kapoor, R. et al. Impact of chemokines CCR5∆32, CXCL12G801A, and CXCR2C1208T on bladder cancer susceptibility in north Indian population. Tumor Biol. 35, 4765–4772 (2014). https://doi.org/10.1007/s13277-014-1624-7
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DOI: https://doi.org/10.1007/s13277-014-1624-7