CCL5-28, CCL5-403, and CCR5 genetic polymorphisms and their synergic effect with alcohol and tobacco consumptions increase susceptibility to hepatocellular carcinoma
First Online: 29 February 2012 Received: 23 December 2011 Accepted: 06 February 2012 DOI:
10.1007/s12032-012-0189-9 Cite this article as: Tsai, H., Yang, S., Chen, D. et al. Med Oncol (2012) 29: 2771. doi:10.1007/s12032-012-0189-9 Abstract
The aim of this study was to estimate the relationship between gene polymorphisms of CCL5-28, CCL5-403, and CCR5 to the susceptibility of hepatocellular carcinoma (HCC). A total of 449 subjects, including 347 healthy controls and 102 patients with HCC, were recruited in this study and subjected to polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) to investigate the impact of these two polymorphic variants on HCC. A significant association between HCC susceptibility and genetic polymorphism, CG heterozygotes of CCL5-28 (AOR = 2.35; 95% CI = 1.27–4.33,
p = 0.006), AA homozygotes of CCL5-403 (AOR = 5.18; 95% CI = 2.25–11.91, p = 0.0001), and AA homozygotes of CCR5 (AOR = 2.47; 95% CI = 1.24–4.90, p = 0.009), was found compared with wild genotype after adjusting for other confounders. It was detected that synergistic effect between gene-to-gene polymorphisms increased the risk to have HCC among individuals with CG or GG of CCL5-28, and GA or AA of CCL-403, and GA or AA of CCR5 (AOR = 3.42; 95% CI = 1.39–8.38, p = 0.007) compared to individuals with wild genotypes of CCL5-28, CCL-403, and CCR5. Also, alcohol or tobacco consumption increased the risk to have HCC among subjects with CG heterozygotes of CCL5-28 (alcohol: p = 0.001; tobacco: p = 0.006), AA homozygotes (alcohol: p = 0.0004; tobacco: p ≤ 0.0001) or GA heterozygotes (tobacco: p = 0.03) of CCL5-403, and AA homozygotes of CCR5 (alcohol: p = 0.02; tobacco: p = 0.02), respectively. Gene polymorphisms of CCL5-28, CCL5-403, and CCR5 play an important factor for the susceptibility of HCC, respectively. The synergic effects of these two gene polymorphisms to tobacco or alcohol consumption significantly increase the risk to develop HCC. Keywords Chemokine ligands CC ligand 5 (CCL5) CC receptor 5 (CCR5) Single nucleotide polymorphism (SNP) Hepatocellular carcinoma (HCC) References
Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9(2):191–211.
Tilakaratne WM, Iqbal Z, Teh MT, Ariyawardana A, Pitiyage G, Cruchley A, Stewart JE, Hagi-Pavli E, Lalli A, Waseem A, et al. Upregulation of HIF-1alpha in malignant transformation of oral submucous fibrosis. J Oral Pathol Med. 2008;37(6):372–7.
Department of Health, Republic of China. Health Statistics: II. Vital Statistics. Taipei: Department of Health; 2007.
Bruix J. Treatment of hepatocellular carcinoma. Hepatology. 1997;25(2):259–62.
Okita K. Management of hepatocellular carcinoma in Japan. J Gastroenterol. 2006;41(2):100–6.
Hao K, Luk JM, Lee NP, Mao M, Zhang C, Ferguson MD, Lamb J, Dai H, Ng IO, Sham PC, et al. Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters. BMC Cancer. 2009;9:389.
Seong J. Challenge and hope in radiotherapy of hepatocellular carcinoma. Yonsei Med J. 2009;50(5):601–12.
Kawata A, Une Y, Hosokawa M, Uchino J, Kobayashi H. Tumor-infiltrating lymphocytes and prognosis of hepatocellular carcinoma. Jpn J Clin Oncol. 1992;22(4):256–63.
Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 1998;27(2):407–14.
Yoong KF, McNab G, Hubscher SG, Adams DH. Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol. 1998;160(8):3978–88.
Yoong KF, Afford SC, Jones R, Aujla P, Qin S, Price K, Hubscher SG, Adams DH. Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Hepatology. 1999;30(1):100–11.
Adams DH, Lloyd AR. Chemokines: leucocyte recruitment and activation cytokines. Lancet. 1997;349(9050):490–5.
Baggiolini M. Chemokines and leukocyte traffic. Nature. 1998;392(6676):565–8.
Liu Y, Poon RT, Feng X, Yu WC, Luk JM, Fan ST. Reduced expression of chemokine receptors on peripheral blood lymphocytes in patients with hepatocellular carcinoma. Am J Gastroenterol. 2004;99(6):1111–21.
Kusano F, Tanaka Y, Marumo F, Sato C. Expression of C–C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C. Lab Invest. 2000;80(3):415–22.
Apolinario A, Majano PL, Alvarez-Perez E, Saez A, Lozano C, Vargas J, Garcia-Monzon C. Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Am J Gastroenterol. 2002;97(11):2861–70.
Liu Y, Poon RT, Hughes J, Feng X, Yu WC, Fan ST. Chemokine receptors support infiltration of lymphocyte subpopulations in human hepatocellular carcinoma. Clin Immunol. 2005;114(2):174–82.
Uekusa Y, Yu WG, Mukai T, Gao P, Yamaguchi N, Murai M, Matsushima K, Obika S, Imanishi T, Higashibata Y, et al. A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice. Cancer Res. 2002;62(13):3751–8.
Mantovani A. Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines. Lab Invest. 1994;71(1):5–16.
Kulbe H, Levinson NR, Balkwill F, Wilson JL. The chemokine network in cancer–much more than directing cell movement. Int J Dev Biol. 2004;48(5–6):489–96.
Sutton A, Friand V, Papy-Garcia D, Dagouassat M, Martin L, Vassy R, Haddad O, Sainte-Catherine O, Kraemer M, Saffar L, et al. Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells. Mol Cancer Ther. 2007;6(11):2948–58.
Charni F, Friand V, Haddad O, Hlawaty H, Martin L, Vassy R, Oudar O, Gattegno L, Charnaux N, Sutton A. Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochim Biophys Acta. 2009;1790(10):1314–26.
Martin L, Blanpain C, Garnier P, Wittamer V, Parmentier M, Vita C. Structural and functional analysis of the RANTES-glycosaminoglycans interactions. Biochemistry. 2001;40(21):6303–18.
Hirano F, Komura K, Fukawa E, Makino I. Tumor necrosis factor alpha (TNF-alpha)-induced RANTES chemokine expression via activation of NF-kappaB and p38 MAP kinase: roles of TNF-alpha in alcoholic liver diseases. J Hepatol. 2003;38(4):483–9.
Kim DH, Jung HD, Lee NY, Sohn SK. Single nucleotide polymorphism of CC chemokine ligand 5 promoter gene in recipients may predict the risk of chronic graft-versus-host disease and its severity after allogeneic transplantation. Transplantation. 2007;84(7):917–25.
Liu H, Chao D, Nakayama EE, Taguchi H, Goto M, Xin X, Takamatsu JK, Saito H, Ishikawa Y, Akaza T, et al. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. Proc Natl Acad Sci USA. 1999;96(8):4581–5.
McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM. CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet. 1998;352(9131):866–70.
Shieh B, Liau YE, Hsieh PS, Yan YP, Wang ST, Li C. Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5 and CXCR4. Int Immunol. 2000;12(9):1311–8.
Centers for Disease Control, Taiwan.
Weng CJ, Chien MH, Lin CW, Chung TT, Zavras AI, Tsai CM, Chen MK, Yang SF. Effect of CC chemokine ligand 5 and CC chemokine receptor 5 genes polymorphisms on the risk and clinicopathological development of oral cancer. Oral Oncol. 2010;46(10):767–72.
Shin EC, Choi YH, Kim JS, Kim SJ, Park JH. Expression patterns of cytokines and chemokines genes in human hepatoma cells. Yonsei Med J. 2002;43(5):657–64.
El-Zayadi AR. Heavy smoking and liver. World J Gastroenterol. 2006;12(38):6098–101.
Hassan MM, Spitz MR, Thomas MB, El-Deeb AS, Glover KY, Nguyen NT, Chan W, Kaseb A, Curley SA, Vauthey JN, et al. Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study. Int J Cancer. 2008;123(8):1883–91.
McKillop IH, Schrum LW. Role of alcohol in liver carcinogenesis. Semin Liver Dis. 2009;29(2):222–32.
Schutte K, Bornschein J, Malfertheiner P. Hepatocellular carcinoma–epidemiological trends and risk factors. Dig Dis. 2009;27(2):80–92.
Hsiao PC, Chen MK, Su SC, Ueng KC, Chen YC, Hsieh YH, Liu YF, Tsai HT, Yang SF. Hypoxia inducible factor-1alpha gene polymorphism G1790A and its interaction with tobacco and alcohol consumptions increase susceptibility to hepatocellular carcinoma. J Surg Oncol. 2012;102(2):163–9.
Maltby J, Wright S, Bird G, Sheron N. Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis. Hepatology. 1996;24(5):1156–60.
Yeligar SM, Machida K, Tsukamoto H, Kalra VK. Ethanol augments RANTES/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1. J Immunol. 2009;183(9):5964–76.
Bukara M, Bautista AP. Acute alcohol intoxication and gadolinium chloride attenuate endotoxin-induced release of CC chemokines in the rat. Alcohol. 2000;20(2):193–203.
Marcondes MC, Watry D, Zandonatti M, Flynn C, Taffe MA, Fox H. Chronic alcohol consumption generates a vulnerable immune environment during early SIV infection in rhesus macaques. Alcohol Clin Exp Res. 2008;32(9):1583–92.
Yamin M, Holbrook EH, Gray ST, Harold R, Busaba N, Sridhar A, Powell KJ, Hamilos DL. Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5 expression in chronic rhinosinusitis. J Allergy Clin Immunol. 2008;122(6):1145–53.
PubMed CrossRef Copyright information
© Springer Science+Business Media, LLC 2012