Molecular Biology Reports

, Volume 35, Issue 3, pp 459–464

Association of HSP70-hom genetic variant with prostate cancer risk

  • Sana Sfar
  • Hamadi Saad
  • Faouzi Mosbah
  • Lotfi Chouchane
Original Paper

Abstract

Because of the importance of androgens to prostate cancer (PCa) development, several candidate genes along androgen pathway have been under intensive study. Given the role of the molecular chaperone HSP70 in the regulation of the androgen receptor (AR) transactivation function, we first chose to explore the association between the HSP70-hom functional genetic variant (+2437 T > C) and prostate cancer risk by genotyping DNA samples from 101 unselected PCa patients and 105 healthy men. There was a trend towards lower frequency of TC and CC genotypes among patients when compared with healthy controls, however the difference did not reach the statistical significance (TC genotype: OR = 0.53, = 0.05; CC genotype: OR = 0.42, = 0.16). Moreover, individuals carrying at least one C allele have a statistically significant lower susceptibility for PCa (OR = 0.51 (0.26–0.97); = 0.02). Since some factors may influence tumor progression rather than initiation, we also examined the relationship between the HSP70-hom polymorphism and the clinical characteristics of the malignancy at the time of diagnosis. The stratified analysis of the genotypes with the clinical stage and tumor grade showed that there was no significant difference in the risk estimates according to prognostic indicators of PCa disease in our population study. This is the first report on the studies of HSP70 SNPs in PCa and our data suggest that this genetic variant may be a genetic marker for PCa susceptibility in Tunisians.

Keywords

Clinical outcome Genetic polymorphism Genetic susceptibility HSP70-hom Prostate cancer 

References

  1. 1.
    ACS (2004) American Cancer Society 2004, AtlantaGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMedCrossRefGoogle 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 343(2):78–85PubMedCrossRefGoogle Scholar
  4. 4.
    Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs WB, Walsh PC (1993) Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150(3):797–802PubMedGoogle Scholar
  5. 5.
    Culig Z, Bartsch G, Hobisch A (2002) Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. Mol Cell Endocrinol 197(1–2):231–238PubMedCrossRefGoogle Scholar
  6. 6.
    Marker PC, Donjacour AA, Dahiya R, Cunha GR (2003) Hormonal, cellular, and molecular control of prostatic development. Dev Biol 253(2):165–174PubMedCrossRefGoogle Scholar
  7. 7.
    Coffey RN, Watson RW, O’Neill AJ, Mc Eleny K, Fitzpatrick JM (2002) Androgen-mediated resistance to apoptosis. Prostate 53(4):300–309PubMedCrossRefGoogle Scholar
  8. 8.
    Kimura K, Markowski M, Bowen C, Gelmann EP (2001) Androgen blocks apoptosis of hormone-dependent prostate cancer cells. Cancer Res 61(14):5611–5618PubMedGoogle Scholar
  9. 9.
    Grossman ME, Huang H, Tindall DJ (2001) Androgen receptor signalling in androgen refractory prostate cancer. J Natl Cancer Inst 93:1687–1697CrossRefGoogle Scholar
  10. 10.
    Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T, Kallioniemi OP (1997) Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 57:314–319PubMedGoogle Scholar
  11. 11.
    Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9(4):401–406PubMedCrossRefGoogle Scholar
  12. 12.
    Miyamoto H, Yeh S, Wilding G, Chang C (1998) Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A 95(13):7379–7384PubMedCrossRefGoogle Scholar
  13. 13.
    Froesch BA, Takayama S, Reed JC (1998) BAG-1L protein enhances androgen receptor function. J Biol Chem 273(19):11660–11666PubMedCrossRefGoogle Scholar
  14. 14.
    Nollen EA, Kabakov AE, Brunsting JF, Kanon B, Höhfeld J, Kampinga HH (2001) Modulation of in vivo HSP70 chaperone activity by Hip and Bag-1. J Biol Chem 276(7):4677–4682PubMedCrossRefGoogle Scholar
  15. 15.
    Knee DA, Froesch BA, Nuber U, Takayama S, Reed JC (2001) Structure-function analysis of Bag1 proteins. Effects on androgen receptor transcriptional activity. J Biol Chem 276(16):12718–12724PubMedCrossRefGoogle Scholar
  16. 16.
    Gassler CS, Wiederkehr T, Brehmer D, Bukau B, Mayer MP (2001) Bag-1 M accelerates nucleotide release for human Hsc70 and Hsp70 and can act concentration-dependent as positive and negative cofactor. J Biol Chem 276(35):32538–32544PubMedCrossRefGoogle Scholar
  17. 17.
    Shatkina L, Mink S, Rogatsch H, Klocker H, Langer G, Nestl A, Cato AC (2003) The cochaperone Bag-1L enhances androgen receptor action via interaction with the NH2-terminal region of the receptor. Mol Cell Biol 23(20):7189–7197PubMedCrossRefGoogle Scholar
  18. 18.
    Guzey M, Takayama S, Reed JC (2000) BAG-1L enhances transactivation function of vitamin D receptor. J Biol Chem 275:40749–40756PubMedCrossRefGoogle Scholar
  19. 19.
    Kaur J, Srivastava A, Ralhan R (1998) Expression of 70-kDa heat shock protein in oral lesions: marker of biological stress or pathogenicity. Oral Oncol 34(6):496–501PubMedCrossRefGoogle Scholar
  20. 20.
    Wei YQ, Zhao X, Kariya Y, Teshigawara K, Uchida A (1995) Inhibition of proliferation and induction of apoptosis by abrogation of heat-shock protein (HSP) 70 expression in tumor cells. Cancer Immunol Immunother 40(2):73–78PubMedCrossRefGoogle Scholar
  21. 21.
    Kaur J, Kaur J, Ralhan R (2000) Induction of apoptosis by abrogation of HSP70 expression in human oral cancer cells. Int J Cancer 85(1):1–5PubMedCrossRefGoogle Scholar
  22. 22.
    Zhao ZG, Shen WL (2005) Heat shock protein 70 antisense oligonucleotide inhibits cell growth and induces apoptosis in human gastric cancer cell line SGC-7901. World J Gastroenterol 11(1):73–78PubMedGoogle Scholar
  23. 23.
    Zhao ZG, Ma QZ, Xu CX (2001) Expression of major heat shock protein 70 in human prostate cancer cell lines PC-3 m and LNCaP and its implication. Clin J Exp Surg 18:169–170Google Scholar
  24. 24.
    Gibbons NB, Watson RW, Coffey RN, Brady HP, Fitzpatrick JM (2000) Heat-shock proteins inhibit induction of prostate cancer cell apoptosis. Prostate 45(1):58–65PubMedCrossRefGoogle Scholar
  25. 25.
    Zhao ZG, Ma QZ, Xu CX (2004) Abrogation of heat-shock protein (HSP)70 expression induced cell growth inhibition and apoptosis in human androgen-independent prostate cancer cell line PC-3 m. Asian J Androl 6(4):319–324PubMedGoogle Scholar
  26. 26.
    Milner CM, Campbell RD (1990) Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32(4):242–251PubMedCrossRefGoogle Scholar
  27. 27.
    Hunt C, Morimoto RI (1985) Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci USA 82(19):6455–6459PubMedCrossRefGoogle Scholar
  28. 28.
    Milner CM, Campbell RD (1992) Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics 36(6):357–362PubMedCrossRefGoogle Scholar
  29. 29.
    Rippmann F, Taylor WR, Rothbard JB, Green NM (1991) A hypothetical model for the peptide binding domain of hsp70 based on the peptide binding domain of HLA. EMBO J 10(5):1053–1059PubMedGoogle Scholar
  30. 30.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRefGoogle Scholar
  31. 31.
    Shields PG, Harris CC (2000) Cancer risk and low-penetrance susceptibility genes in gene-environment interactions. J Clin Oncol 18(11):2309–2315PubMedGoogle Scholar
  32. 32.
    Pociot F, Ronningen KS, Nerup J (1993) Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70–2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). Scand J Immunol 38(5):491–495PubMedCrossRefGoogle Scholar
  33. 33.
    Westman P, Partanen J, Leirisalo-Repo M, Koskimies S (1994) HSP70-Hom NcoI polymorphism and HLA-associations in the Finnish population and in patients with ankylosing spondylitis or reactive arthritis. Eur J Immunogenet 21(2):81–90PubMedCrossRefGoogle Scholar
  34. 34.
    Meddeb-Garnaoui A, Gritli S, Garbouj S, Ben Fadhel M, El Kares R, Mansour L, Kaabi B, Chouchane L, Ben Salah A, Dellagi K (2001) Association analysis of HLA-class II and class III gene polymorphisms in the susceptibility to mediterranean visceral leishmaniasis. Hum Immunol 62(5):509–517PubMedCrossRefGoogle Scholar
  35. 35.
    Vargas-Alarcon G, Londono JD, Hernandez-Pacheco G, Gamboa R, Castillo E, Pacheco-Tena C, Cardiel MH, Granados J, Burgos-Vargas R (2002) Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies. Ann Rheum Dis 61(1):48–51PubMedCrossRefGoogle Scholar
  36. 36.
    Martin AM, Nolan D, Gaudieri S, Almeida CA, Nolan R, James I, Carvalho F, Phillips E, Christiansen FT, Purcell AW, McCluskey J, Mallal S. (2004) Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci U S A 101(12):4180–4185PubMedCrossRefGoogle Scholar
  37. 37.
    Bogunia-Kubik K, Lange A (2005) HSP70-hom gene polymorphism in allogeneic hematopoietic stem-cell transplant recipients correlates with the development of acute graft-versus-host disease. Transplantation 79(7):815–820PubMedCrossRefGoogle Scholar
  38. 38.
    Zhou F, Wang F, Li F, Yuan J, Zeng H, Wei Q, Tanguay RM, Wu T (2005) Association of hsp70–2 and hsp-hom gene polymorphisms with risk of acute high-altitude illness in a Chinese population. Cell Stress Chaperones 10(4):349–356PubMedCrossRefGoogle Scholar
  39. 39.
    Bogunia-Kubik K, Koscinska K, Suchnicki K, Lange A (2006) HSP70-hom gene single nucleotide (+2763 G/A and +2437 C/T) polymorphisms in sarcoidosis. Int J Immunogenet 33(2):135–140PubMedCrossRefGoogle Scholar
  40. 40.
    Bogunia-Kubik K, Uklejewska A, Dickinson A, Jarvis M, Lange A (2006) HSP70-hom gene polymorphism as a prognostic marker of graft-versus-host disease. Transplantation 82(8):1116–1117PubMedCrossRefGoogle Scholar
  41. 41.
    Chouchane L, Ahmed SB, Baccouche S, Remadi S. (1997) Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors. Cancer 80(8):1489–1496PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Sana Sfar
    • 1
  • Hamadi Saad
    • 2
  • Faouzi Mosbah
    • 3
  • Lotfi Chouchane
    • 1
  1. 1.Department of Molecular Immuno-OncologyFaculty of MedicineMonastirTunisia
  2. 2.Department of UrologyEPS Fattouma BourguibaMonastirTunisia
  3. 3.Department of UrologyEPS SahloulSousseTunisia

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