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Journal of Cancer Research and Clinical Oncology

, Volume 133, Issue 11, pp 859–866 | Cite as

Importance of polymorphisms in NF-κB1 and NF-κBIα genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients

  • Huajie Bu
  • Inger Rosdahl
  • Xiao-Feng Sun
  • Hong ZhangEmail author
Original Paper

Abstract

Purpose

Importance of polymorphisms in NF-κB1 and NF-κBIα genes for melanoma risk, clinicopathological features and tumor progression is analyzed in Swedish melanoma patients.

Patients and methods

Functional polymorphisms of NF-κB1 and NF-κBIα genes were examined in 185 melanoma patients and 438 tumor-free individuals. Associations of the polymorphisms with melanoma risk, age and pigment phenotypes of the patients and clinicopathological tumor characteristics were analyzed. DNAs were isolated from mononuclear cells of venous blood. Polymorphisms of the genes were genotyped by a PCR-RFLP technique, and transcription level of NF-κBIα was examined by a quantitative real-time reverse transcription PCR.

Results

Both ATTG insertion polymorphism of NF-κB1 and A to G polymorphism of NF-κBIα genes were correlated with melanoma risk, especially, in a combination of ATTG 2 /ATTGT2 and GG. NF-κB1 ATTG2/ATTG2 and NF-κBIα GG genotypes were associated with male gender and age >65 years (at diagnosis). Patients with ATTG1/ATTG1 genotype had thinner tumors and lower Clark levels at diagnosis. Frequency of ATTG1/ATTG1 genotype was higher in patients with melanomas on intermittently sun-exposed pattern of the body and NF-κBIα GG was more frequent in the patients with melanomas at rarely exposed sites. There were no differences in the gene transcription level between patients with different NF-κBIα genotypes.

Conclusion

NF-κB1 and NF-κBIα genes might be susceptible genes for melanoma risk and functional polymorphisms of these genes might be biological predictors for melanoma progression.

Keywords

Polymorphisms NF-κB1 NF-κBIα Melanoma risk Clinicopathological features Phenotypes 

Notes

Acknowledgments

The authors are grateful to Mona-Lisa Sandh from the Department of Dermatology, Linköping University Hospital, Drs. Kenneth Lagmo and Eva Niklasson from the Dermatology Out-patient Clinic, Linköping, and the melanoma patients who participated in this study. The study was supported by Edward Welander Finsen Foundation, Cancer and Allergy Foundation and Research Council in the South-East of Sweden

References

  1. Amiri KI, Richmond A (2005) Role of nuclear factor-kappa B in melanoma. Cancer Metastasis Rev 24(2):301–313PubMedCrossRefGoogle Scholar
  2. Balch CM, Soong SJ et al (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19(16):3622–3634PubMedGoogle Scholar
  3. Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683PubMedCrossRefGoogle Scholar
  4. Bartkova J, Lukas J et al (1996) The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res 56(23):5475–5483PubMedGoogle Scholar
  5. Becker TM, Rizos H et al (2005) Impaired inhibition of NF-kappaB activity by melanoma-associated p16INK4a mutations. Biochem Biophys Res Commun 332(3):873–879PubMedCrossRefGoogle Scholar
  6. Biswas DK, Cruz AP et al (2000) Epidermal growth factor-induced nuclear factor kappa B activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci 97(15):8542–8547PubMedCrossRefGoogle Scholar
  7. Campbell KJ, Perkins ND (2006) Regulation of NF-kappaB function. Biochem Soc Symp 73:165–180PubMedGoogle Scholar
  8. Chin L (2003) The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer 3(8):559–570PubMedCrossRefGoogle Scholar
  9. Curran JE, Weinstein SR et al (2002) Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their involvement in sporadic breast cancer. Cancer Lett 188(1–2):103–107PubMedCrossRefGoogle Scholar
  10. Dolcet X, Llobet D et al (2005) NF-kB in development and progression of human cancer. Virchows Arch 446(5):475–482PubMedCrossRefGoogle Scholar
  11. Feinman R, Siegel DS et al (2004) Regulation of NF-kB in multiple myeloma: therapeutic implications. Clin Adv Hematol Oncol 2(3):162–166PubMedGoogle Scholar
  12. Gilmore TD (2003) The Re1/NF-kappa B/I kappa B signal transduction pathway and cancer. Cancer Treat Res 115:241–265PubMedCrossRefGoogle Scholar
  13. Glavac D, Ravnik-Glavac M et al (1994) Polymorphisms in the 3′ untranslated region of the I kappa B/MAD-3 (NFKBI) gene located on chromosome 14. Hum Genet 93(6):694–696PubMedCrossRefGoogle Scholar
  14. Goto Y, Yue L et al (2001) A novel single-nucleotide polymorphism in the 3′-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res 7(7):1952–1956PubMedGoogle Scholar
  15. Greenlee RT, Hill-Harmon MB et al (2001) Cancer statistics, 2001. CA Cancer J Clin 51(1):15–36PubMedGoogle Scholar
  16. Haluska FG, Housman DE (1995) Recent advances in the molecular genetics of malignant melanoma. Cancer Surv 25:277–292PubMedGoogle Scholar
  17. Houghton AN, Viola MV (1981) Solar radiation and malignant melanoma of the skin. J Am Acad Dermatol 5(4):477–483PubMedGoogle Scholar
  18. Huang S, DeGuzman A et al (2000a) Level of interleukin-8 expression by metastatic human melanoma cells directly correlates with constitutive NF-kappaB activity. Cytokines Cell Mol Ther 6(1):9–17PubMedCrossRefGoogle Scholar
  19. Huang S, DeGuzman A et al (2000b) Nuclear factor-kappaB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res 6(6):2573–2578PubMedGoogle Scholar
  20. Huang S, Robinson JB et al (2000c) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60(19):5334–5339PubMedGoogle Scholar
  21. Karban AS, Okazaki T et al (2004) Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 13(1):35–45PubMedCrossRefGoogle Scholar
  22. Kim LH, Shin HD et al (2003) Identification of variants in NFKBIA and association analysis with hepatocellular carcinoma risk among chronic HBV patients. Hum Mutat 21(6):652–653PubMedCrossRefGoogle Scholar
  23. Lin SC, Liu CJ et al (2006) Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers. Cancer Lett 243(1):45–47CrossRefGoogle Scholar
  24. Mackie RM, Smyth JF et al (1985) Malignant melanoma in Scotland 1979–1983. Lancet 2(8460):859–863PubMedCrossRefGoogle Scholar
  25. Piepkorn MW (1994) Genetic basis of susceptibility to melanoma. J Am Acad Dermatol 31(6):1022–1039PubMedCrossRefGoogle Scholar
  26. Richmond A (2002) Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2(9):664–674PubMedCrossRefGoogle Scholar
  27. Shahbazi M, Pravica V et al (2002) Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359(9304):397–401PubMedCrossRefGoogle Scholar
  28. Shattuck-Brandt RL, Richmond A (1997) Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. Cancer Res 57(14):3032–3039PubMedGoogle Scholar
  29. Simon MM, Aragane Y et al (1994) UVB light induces nuclear factor kappa B (NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts. J Invest Dermatol 102(4):422–427PubMedCrossRefGoogle Scholar
  30. Stierner U, Augustsson A et al (1991) Regional distribution of common and dysplastic naevi in relation to melanoma site and sun exposure. A case-control study. Melanoma Res 1(5–6):367–375Google Scholar
  31. Ueda Y, Richmond A (2006) NF-kappaB activation in melanoma. Pigment Cell Res 19(2):112–124PubMedCrossRefGoogle Scholar
  32. Winnepenninckx V, Lazer V et al (2006) Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 98(7):472–482PubMedCrossRefGoogle Scholar
  33. Yang J, Richmond A (2001) Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res 61(12):4901–4909PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Huajie Bu
    • 1
  • Inger Rosdahl
    • 1
  • Xiao-Feng Sun
    • 2
  • Hong Zhang
    • 1
    Email author
  1. 1.Department of Dermatology, Institute of Biomedicine and SurgeryLinköping UniversityLinköpingSweden
  2. 2.Department of Oncology, Institute of Biomedicine and SurgeryLinköping UniversityLinköpingSweden

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