Molecular Biology Reports

, Volume 39, Issue 12, pp 11073–11079 | Cite as

Association between SDF1-3′A or CXCR4 gene polymorphisms with predisposition to and clinicopathological characteristics of prostate cancer with or without metastases

  • Ferruh K. İşman
  • Canan Kucukgergin
  • Selçuk Daşdemir
  • Bedia Cakmakoglu
  • Oner Sanli
  • Sule Seckin


In the present study, we aimed to investigate the association between SDF1-3′A and CXCR4 gene polymorphisms and the susceptibility and clinicopathological development of prostate cancer. SDF1-3′A and CXCR4 gene polymorphisms were assessed by polymerase chain reaction restriction-fragment length polymorphism (PCR–RFLP) in 149 healthy subjects and 152 patients with prostate cancer. There were no significant differences in the distributions of SDF-1 and CXCR4 genotypes between controls and prostate cancer patients. However, the patients with AA genotype of SDF1-3′A gene presented a higher risk for developing an advanced disease status as compared to patients with GG homozygotes (aOR = 2.02; 95 % CI = 1.05-3.90; P = 0.035). In addition, the distribution of AA genotype of SDF1-3′A gene was found significantly increased in the patients with bone metastasis in comparison to those without bone metastasis (aOR = 2.94; 95 % CI = 1.26-6.82; P = 0.012). On the other hand, CXCR4 gene polymorphism was not associated with the clinicopathological characteristics of prostate cancer. Our results suggest that SDF1-3′A and CXCR4 gene polymorphisms may not be risk factors for the susceptibility to prostate cancer. However, SDF1-3′A gene polymorphism may be associated with the progression and bone metastasis of prostate cancer in a Turkish men population.


SDF-1(CXCL12) CXCR4 Single nucleotide polymorphism PCR–RFLP analysis Prostate cancer 



This work was supported by the Research Fund of Istanbul University. Project no. 12204.


  1. 1.
    Collin SM, Martin RM, Metcalfe C, Gunnell D, Albertsen PC, Neal D, Hamdy F, Stephens P, Lane JA, Moore R, Donovan J (2008) Prostate-cancer mortality in the USA and UK in 1975–2004: an ecological study. Lancet Oncol 9:445–452PubMedCrossRefGoogle Scholar
  2. 2.
    Akashi T, Koizumi K, Tsuneyama K, Saiki I, Takano Y, Fuse H (2008) Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci 99:539–542PubMedCrossRefGoogle Scholar
  3. 3.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 13:78–85CrossRefGoogle Scholar
  4. 4.
    De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG (2007) Inflammation in prostate carcinogenesis. Nat Rev Cancer 7:256–269PubMedCrossRefGoogle Scholar
  5. 5.
    Ruffini PA, Morandi P, Cabioglu N, Altundag K, Cristofanilli M (2007) Manipulating the chemokine–chemokine receptor network to treat cancer. Cancer 109:2392–2404PubMedCrossRefGoogle Scholar
  6. 6.
    Singh S, Sadanandam A, Singh RK (2007) Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev 26:453–467PubMedCrossRefGoogle Scholar
  7. 7.
    Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56PubMedCrossRefGoogle Scholar
  8. 8.
    Lee BC, Lee TH, Avraham S, Avraham HK (2004) Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2:327–338PubMedGoogle Scholar
  9. 9.
    Luker KE, Luker GD (2006) Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 238:30–41PubMedCrossRefGoogle Scholar
  10. 10.
    Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62:1832–1837PubMedGoogle Scholar
  11. 11.
    Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, Taichman RS (2003) Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem 89:462–473PubMedCrossRefGoogle Scholar
  12. 12.
    Uchida D, Begum NM, Tomizuka Y, Bando T, Almofti A, Yoshida H, Sato M (2004) Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma. Lab Invest 84:1538–1546PubMedCrossRefGoogle Scholar
  13. 13.
    Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O’Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O’Brien SJ (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 279:389–393PubMedCrossRefGoogle Scholar
  14. 14.
    Soriano A, Martínez C, García F, Plana M, Palou E, Lejeune M, Aróstegui JI, De Lazzari E, Rodriguez C, Barrasa A, Lorenzo JI, Alcamí J, del Romero J, Miró JM, Gatell JM, Gallart T (2002) Plasma stromal cell-derived factor (SDF)-1 levels, SDF1-3′A genotype, and expression of CXCR4 on T lymphocytes: their impact on resistance to human immunodeficiency virus type 1 infection and its progression. J Infect Dis 186:922–931PubMedCrossRefGoogle Scholar
  15. 15.
    Petersen DC, Glashoff RH, Shrestha S, Bergeron J, Laten A, Gold B, van Rensburg EJ, Dean M, Hayes VM (2005) Risk for HIV-1 infection associated with a common CXCL12 (SDF1) polymorphism and CXCR4 variation in an African population. J Acquir Immune Defic Syndr 40:521–526PubMedCrossRefGoogle Scholar
  16. 16.
    Zafiropoulos A, Crikas N, Passam AM, Spandidos DA (2004) Significant involvement of CCR2-64I and CXCL12-3a in the development of sporadic breast cancer. J Med Genet 41:59CrossRefGoogle Scholar
  17. 17.
    Maley SN, Schwartz SM, Johnson LG, Malkki M, Du Q, Daling JR, Li SS, Zhao LP, Petersdorf EW, Madeleine MM (2009) Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study. Int J Immunogenet 36:367–375PubMedCrossRefGoogle Scholar
  18. 18.
    Shen W, Cao X, Xi L, Deng L (2011) CXCL12 G801A polymorphism and breast cancer risk: a meta-analysis. Mol Biol Rep 39:2039–2044PubMedCrossRefGoogle Scholar
  19. 19.
    Razmkhah M, Doroudchi M, Ghayumi SM, Erfani N, Ghaderi A (2005) Stromal cell-derived factor-1 (SDF-1) gene and susceptibility of Iranian patients with lung cancer. Lung Cancer 49:311–315PubMedCrossRefGoogle Scholar
  20. 20.
    Hidalgo-Pascual M, Galan JJ, Chaves-Conde M, Ramírez-Armengol JA, Moreno C, Calvo E, Pelaez P, Crespo C, Ruiz A, Royo JL (2007) Analysis of CXCL12 3′UTR G>A polymorphism in colorectal cancer. Oncol Rep 18:1583–1587PubMedGoogle Scholar
  21. 21.
    Lee YL, Kuo WH, Lin CW, Chen W, Cheng WE, Chen SC, Shih CM (2011) Association of genetic polymorphisms of CXCL12/SDF1 gene and its receptor, CXCR4, to the susceptibility and prognosis of non-small cell lung cancer. Lung Cancer 73:147–152PubMedCrossRefGoogle Scholar
  22. 22.
    Cacina C, Bulgurcuoglu-Kuran S, Iyibozkurt AC, Yaylim-Eraltan I, Cakmakoglu B (2011) Genetic variants of SDF-1 and CXCR4 genes in endometrial carcinoma. Mol Biol Rep 39:1225–1229PubMedCrossRefGoogle Scholar
  23. 23.
    Coelho A, Calçada C, Catarino R, Pinto D, Fonseca G, Medeiros R (2006) CXCL12-3′ A polymorphism and lung cancer metastases protection: new perspectives in immunotherapy? Cancer Immunol Immunother 55:639–643PubMedCrossRefGoogle Scholar
  24. 24.
    Teng YH, Liu TH, Tseng HC, Chung TT, Yeh CM, Li YC, Ou YH, Lin LY, Tsai HT, Yang SF (2009) Contribution of genetic polymorphisms of stromal cell-derived factor-1 and its receptor, CXCR4, to the susceptibility and clinicopathologic development of oral cancer. Head Neck 31:1282–1288PubMedCrossRefGoogle Scholar
  25. 25.
    Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, Ravetti JL, Zona G, Spaziante R, Corte G, Schettini G, Florio T (2006) Expression of CXC chemokine receptors 1–5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 49:423–432PubMedCrossRefGoogle Scholar
  26. 26.
    Xing Y, Liu M, Du Y, Qu F, Li Y, Zhang Q, Xiao Y, Zhao J, Zeng F, Xiao C (2008) Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdown: a possible metastasis preventing and minimizing approach. Cancer Biol Ther 7:1839–1848PubMedCrossRefGoogle Scholar
  27. 27.
    Engl T, Relja B, Blumenberg C, Müller I, Ringel EM, Beecken WD, Jonas D, Blaheta RA (2006) Prostate tumor CXC-chemokine profile correlates with cell adhesion to endothelium and extracellular matrix. Life Sci 78:1784–1793PubMedCrossRefGoogle Scholar
  28. 28.
    Sun YX, Fang M, Wang J, Cooper CR, Pienta KJ, Taichman RS (2007) Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate 67:61–73PubMedCrossRefGoogle Scholar
  29. 29.
    Vaday GG, Hua SB, Peehl DM, Pauling MH, Lin YH, Zhu L, Lawrence DM, Foda HD, Zucker S (2004) CXCR4 and CXCL12 (SDF-1) in prostate cancer: inhibitory effects of human single chain Fv antibodies. Clin Cancer Res 10:5630–5639PubMedCrossRefGoogle Scholar
  30. 30.
    Engl T, Relja B, Marian D, Blumenberg C, Müller I, Beecken WD, Jones J, Ringel EM, Bereiter-Hahn J, Jonas D, Blaheta RA (2006) CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8:290–301PubMedCrossRefGoogle Scholar
  31. 31.
    Sun YX, Schneider A, Jung Y, Wang J, Dai J, Wang J, Cook K, Osman NI, Koh-Paige AJ, Shim H, Pienta KJ, Keller ET, McCauley LK, Taichman RS (2005) Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res 20:318–329PubMedCrossRefGoogle Scholar
  32. 32.
    Mori T, Doi R, Koizumi M, Toyoda E, Ito D, Kami K, Masui T, Fujimoto K, Tamamura H, Hiramatsu K, Fujii N, Imamura M (2004) CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther 3:29–37PubMedCrossRefGoogle Scholar
  33. 33.
    Hirata H, Hinoda Y, Kikuno N, Kawamoto K, Dahiya AV, Suehiro Y, Tanaka Y, Dahiya R (2007) CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin Cancer Res 13:5056–5062PubMedCrossRefGoogle Scholar
  34. 34.
    De Oliveira KB, Oda JM, Voltarelli JC, Nasser TF, Ono MA, Fujita TC, Matsuo T, Watanabe MA (2009) CXCL12 rs1801157 polymorphism in patients with breast cancer, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma. J Clin Lab Anal 23:387–393PubMedCrossRefGoogle Scholar
  35. 35.
    Kruszyna L, Lianeri M, Rydzanicz M, Szyfter K, Jagodziński PP (2010) SDF1-3′ a gene polymorphism is associated with laryngeal cancer. Pathol Oncol Res 16:223–227PubMedCrossRefGoogle Scholar
  36. 36.
    Chang CC, Chen SC, Hsieh YH, Chen YC, Chen TY, Chu YH, Ma HJ, Chou MC, Tsai HT, Yang SF (2009) Stromal cell-derived factor-1 but not its receptor, CXCR4, gene variants increase susceptibility and pathological development of hepatocellular carcinoma. Clin Chem Lab Med 47:412–418PubMedCrossRefGoogle Scholar
  37. 37.
    Vairaktaris E, Vylliotis A, Spyridonodou S, Derka S, Vassiliou S, Nkenke E, Yapijakis C, Serefoglou Z, Neukam FW, Patsouris E (2008) A DNA polymorphism of stromal-derived factor-1 is associated with advanced stages of oral cancer. Anticancer Res 28:271–275PubMedGoogle Scholar
  38. 38.
    Vergis R, Corbishley CM, Norman AR, Bartlett J, Jhavar S, Borre M, Heeboll S, Horwich A, Huddart R, Khoo V, Eeles R, Cooper C, Sydes M, Dearnaley D, Parker C (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9:342–351PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Q, Diao X, Sun J, Chen Z (2011) Regulation of VEGF, MMP-9 and metastasis by CXCR4 in a prostate cancer cell line. Cell Biol Int 35:897–904PubMedCrossRefGoogle Scholar
  40. 40.
    Fujino H, Kondo K, Ishikura H, Maki H, Kinoshita H, Miyoshi T, Takahashi Y, Sawada N, Takizawa H, Nagao T, Sakiyama S, Monden Y (2005) Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer. Mol Cancer Ther 4:1409–1416PubMedCrossRefGoogle Scholar
  41. 41.
    Hanyu A, Kojima K, Hatake K, Nomura K, Murayama H, Ishikawa Y, Miyata S, Ushijima M, Matsuura M, Ogata E, Miyazawa K, Imamura T (2009) Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti-human VEGF antibody in xenograft model of human fibrosarcoma HT1080 cells. Cancer Sci 100:2085–2092PubMedCrossRefGoogle Scholar
  42. 42.
    De Nigris F, Crudele V, Giovane A, Casamassimi A, Giordano A, Garban HJ, Cacciatore F, Pentimalli F, Marquez-Garban DC, Petrillo A, Cito L, Sommese L, Fiore A, Petrillo M, Siani A, Barbieri A, Arra C, Rengo F, Hayashi T, Al-Omran M, Ignarro LJ, Napoli C (2010) CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proc Natl Acad Sci USA 107:14484–14489PubMedCrossRefGoogle Scholar
  43. 43.
    Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, Cher ML (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate 66:32–48PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Ferruh K. İşman
    • 1
  • Canan Kucukgergin
    • 2
  • Selçuk Daşdemir
    • 3
  • Bedia Cakmakoglu
    • 3
  • Oner Sanli
    • 4
  • Sule Seckin
    • 2
  1. 1.Clinical Biochemistry LaboratoryGoztepe Teaching and Research HospitalIstanbulTurkey
  2. 2.Department of Biochemistry, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
  3. 3.Department of Molecular Medicine, Institute for Experimental Medicine ResearchIstanbul UniversityIstanbulTurkey
  4. 4.Department of Urology, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

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