Skip to main content

Advertisement

SpringerLink
Log in

The single nucleotide polymorphism g.1548A >G (K469E) of the ICAM-1 gene is associated with worse prognosis in non-small cell lung cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Intercellular adhesion molecule-1 (ICAM-1), a cell adhesion molecule with a key role in inflammation and immunosurveillance, has been implicated in carcinogenesis by facilitating instability of the tumor environment. The K469E single nucleotide polymorphism (SNP) (G>A) affects the ICAM-1 mRNA splicing pattern; the alternatively spliced isoform (ICAM-1-S) lacks transmembrane and intracellular domain, which affects the structural and signal transduction properties. Moreover, the expression of ICAM-1 is transcriptionally regulated by p53, and this SNP has been shown to be related with apoptosis. PCR-RFLP analysis was used to assess the K469E SNP status comparatively in 203 non-small cell lung cancer patients and 175 healthy sex-matched controls. This SNP was examined in relation to tumor kinetic parameters (Ki-67 immunohistochemical evaluation and Tdt-mediated dUTP nick end labeling assay), p53 immunohistochemistry status, and clinicopathological data in patients with operable stages. Both the genotype and allele frequency did not differ significantly between patients and controls. However, patients with the AG/AA genotypes had worse survival (39 vs 45 months, p = 0.036) and tended to be present in advanced stages (p = 0.057). Moreover, the AG/AA genotypes exerted a synergistic effect with aberrant p53 on tumor progression, while the GG genotype retained a better apoptotic index. The AG/AA genotypes correlated with worse survival and advanced stages probably due to defective immunosurveillance and apoptosis. These genetic backgrounds may confer a selective advantage for dissemination of tumor cells with high metastatic potential compared to GG genotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hubbard AK, Rothlein R. Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. Free Radic Biol Med. 2000;28:1379–86.

    Article  CAS  PubMed  Google Scholar 

  2. Yasuda M, Tanaka Y, Tamura M, Fujii K, Sugaya M, So T, Takenoyama M, Yasumoto K. Stimulation of beta1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase. Cancer Res. 2001;61:2022–30.

    CAS  PubMed  Google Scholar 

  3. Anikeeva N, Somersalo K, Sims TN, Thomas VK, Dustin ML, Sykulev Y. Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc Natl Acad Sci USA. 2005;102:6437–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Roland CL, Harken AH, Sarr MG, Barnett Jr CC. ICAM-1 expression determines malignant potential of cancer. Surgery. 2007;141:705–7.

    Article  PubMed  Google Scholar 

  5. Lin YC, Shun CT, Wu MS, Chen CC. A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappa b. Clin Cancer Res. 2006;12:7165–73.

    Article  CAS  PubMed  Google Scholar 

  6. Rosette C, Roth RB, Oeth P, Braun A, Kammerer S, Ekblom J, Denissenko MF. Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis. 2005;26:943–50.

    Article  CAS  PubMed  Google Scholar 

  7. Hayes SH, Seigel GM. Immunoreactivity of ICAM-1 in human tumors, metastases and normal tissues. Int J Clin Exp Pathol. 2009;2:553–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Brooks KJ, Coleman EJ, Vitetta ES. The antitumor activity of an anti-cd54 antibody in SCID mice xenografted with human breast, prostate, non-small cell lung, and pancreatic tumor cell lines. Int J Cancer. 2008;123:2438–45.

    Article  CAS  PubMed  Google Scholar 

  9. Mendez MP, Morris SB, Wilcoxen S, Du M, Monroy YK, Remmer H, Murphy H, Christensen PJ, Paine 3rd R. Disparate mechanisms of SICAM-1 production in the peripheral lung: contrast between alveolar epithelial cells and pulmonary microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2008;294:L807–14.

    Article  CAS  PubMed  Google Scholar 

  10. Hu X, Barnum SR, Wohler JE, Schoeb TR, Bullard DC. Differential ICAM-1 isoform expression regulates the development and progression of experimental autoimmune encephalomyelitis. Mol Immunol. 2010;47:1692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guney N, Soydinc HO, Derin D, Tas F, Camlica H, Duranyildiz D, Yasasever V, Topuz E. Serum levels of intercellular adhesion molecule ICAM-1 and e-selectin in advanced stage non-small cell lung cancer. Med Oncol. 2008;25:194–200.

    Article  CAS  PubMed  Google Scholar 

  12. Sprenger A, Schardt C, Rotsch M, Zehrer M, Wolf M, Havemann K, Heymanns J. Soluble intercellular adhesion molecule-1 in patients with lung cancer and benign lung diseases. J Cancer Res Clin Oncol. 1997;123:632–8.

    Article  CAS  PubMed  Google Scholar 

  13. Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab–an Eastern Cooperative Oncology Group study. Clin Cancer Res. 2008;14:1407–12.

    Article  CAS  PubMed  Google Scholar 

  14. Iwao M, Morisaki H, Morisaki T. Single-nucleotide polymorphism g.1548g>a (e469k) in human ICAM-1 gene affects mRNA splicing pattern and TPA-induced apoptosis. Biochem Biophys Res Commun. 2004;317:729–35.

    Article  CAS  PubMed  Google Scholar 

  15. Holder AL, Wolf S, Walshe C, Pandya P, Stanford RE, Smith JD, Rose ML, Lawson C. Expression of endothelial intercellular adhesion molecule-1 is determined by genotype: effects on efficiency of leukocyte adhesion to human endothelial cells. Hum Immunol. 2008;69:71–8.

    Article  CAS  PubMed  Google Scholar 

  16. Sanadgol N, Nikravesh A, Motalleb G, Roshanzamir F, Balazade T, Ramroodi N, Khajeh H. Evaluation of the association between ICAM-1 gene polymorphisms and SICAM-1 serum levels in multiple sclerosis (MS) patients in Southeast Iran. Int J Genet Mol Biol. 2011;3:81–6. doi:http://www.academicjournals.org/journal/IJGMB/article-abstract/EC5B8CB2675.

    Google Scholar 

  17. Gorgoulis VG, Zacharatos P, Kotsinas A, Kletsas D, Mariatos G, Zoumpourlis V, Ryan KM, Kittas C, Papavassiliou AG. P53 activates ICAM-1 (cd54) expression in an nf-kappab-independent manner. EMBO J. 2003;22:1567–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arandi N, Talei A, Erfani N, Ghaderi A. Intercellular adhesion molecule-1 genetic markers (+241g/a and +469a/g) in Iranian women with breast cancer. Cancer Genet Cytogenet. 2008;183:9–13.

    Article  CAS  PubMed  Google Scholar 

  19. Howell WM, Rose-Zerilli MJ, Theaker JM, Bateman AC. ICAM-1 polymorphisms and development of cutaneous malignant melanoma. Int J Immunogenet. 2005;32:367–73.

    Article  CAS  PubMed  Google Scholar 

  20. Theodoropoulos G, Papaconstantinou I, Felekouras E, Nikiteas N, Karakitsos P, Panoussopoulos D, Lazaris A, Patsouris E, Bramis J, Gazouli M. Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. World J Gastroenterol. 2006;12:5037–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Burim RV, Teixeira SA, Colli BO, Peria FM, Tirapelli LF, Marie SK, Malheiros SM, Oba-Shinjo SM, Gabbai AA, Lotufo PA, Carlotti-Junior CG. ICAM-1 (lys469glu) and PECAM-1 (leu125val) polymorphisms in diffuse astrocytomas. Clin Exp Med. 2009;9:157–63.

    Article  CAS  PubMed  Google Scholar 

  22. Chen H, Hernandez W, Shriver MD, Ahaghotu CA, Kittles RA. ICAM gene cluster SNPs and prostate cancer risk in African Americans. Hum Genet. 2006;120:69–76.

    Article  CAS  PubMed  Google Scholar 

  23. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio Jr RA, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907–13.

    Article  CAS  PubMed  Google Scholar 

  24. Kotsinas A, Evangelou K, Sideridou M, Kotzamanis G, Constantinides C, Zavras AI, Douglass CW, Papavassiliou AG, Gorgoulis VG. The 3′ utr igf2r-a2/b2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer. Cancer Lett. 2008;259:177–85.

    Article  CAS  PubMed  Google Scholar 

  25. Edge SBBD, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. Berlin: Springer; 2010. 646 pp.

    Google Scholar 

  26. Gbadegesin RA, Watson CJ, Cotton SA, Brenchley PE, Webb NJ. A PCR-RFLP typing method for adhesion molecule gene polymorphisms and allele frequencies in a normal UK population. Eur J Immunogenet. 2002;29:109–11.

    Article  CAS  PubMed  Google Scholar 

  27. Cox DG, Hankinson SE, Hunter DJ. Polymorphisms in the ICAM gene locus are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2006;15:178–9.

    Article  CAS  PubMed  Google Scholar 

  28. Kammerer S, Roth RB, Reneland R, Marnellos G, Hoyal CR, Markward NJ, Ebner F, Kiechle M, Schwarz-Boeger U, Griffiths LR, Ulbrich C, Chrobok K, Forster G, Praetorius GM, Meyer P, Rehbock J, Cantor CR, Nelson MR, Braun A. Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus. Cancer Res. 2004;64:8906–10.

    Article  CAS  PubMed  Google Scholar 

  29. Lu ZX, Jiang P, Cai JJ, Xing Y. Context-dependent robustness to 5′ splice site polymorphisms in human populations. Hum Mol Genet. 2011;20:1084–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oh HM, Lee S, Na BR, Wee H, Kim SH, Choi SC, Lee KM, Jun CD. RKIKK motif in the intracellular domain is critical for spatial and dynamic organization of ICAM-1: functional implication for the leukocyte adhesion and transmigration. Mol Biol Cell. 2007;18:2322–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Greenwood J, Amos CL, Walters CE, Couraud PO, Lyck R, Engelhardt B, Adamson P. Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for t lymphocyte-mediated signaling and migration. J Immunol. 2003;171:2099–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M, Tan TG, Zheng L, Ong LC, Jin Y, Kato M, Prevost-Blondel A, Chow P, Yang H, Abastado JP. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest. 2010;120:2030–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gho YS, Kim PN, Li HC, Elkin M, Kleinman HK. Stimulation of tumor growth by human soluble intercellular adhesion molecule-1. Cancer Res. 2001;61:4253–7.

    CAS  PubMed  Google Scholar 

  34. Lane DP. Cancer. P53, guardian of the genome. Nature. 1992;358:15–6.

    Article  CAS  PubMed  Google Scholar 

  35. Hunter KW. Host genetics and tumour metastasis. Br J Cancer. 2004;90:752–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lewis JM, Truong TN, Schwartz MA. Integrins regulate the apoptotic response to DNA damage through modulation of p53. Proc Natl Acad Sci USA. 2002;99:3627–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the European Commission FP7 projects INFLA-CARE (contract no. 223151), INsPiRE (contract no. 284460; REGPOT), the NKUA SARG grant no. 70/3/8916 and the “Hellenic Society of Medical Oncologists” grant (E. Thanopoulou). Both funding sources had no involvement, neither in the conduct of research nor in the preparation of the article.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Goudi, Athens, GR-11527, Greece

    Eirini Thanopoulou, George Kotzamanis, Ioannis S. Pateras, Alexandros Papalambros, Athanassios Kotsinas & Vassilis G. Gorgoulis

  2. 2nd Department of Medical Oncology, Metaxa Hospital, Piraeus, Greece

    Nicholaos Ziras

  3. Department of Histology–Embryology–Anatomy, Nursing School, University of Athens, Athens, Greece

    Theodoros Mariolis-Sapsakos

  4. 1st Department of Propaedeutic Surgery, Hippocrateion Hospital, Medical School, University of Athens, Athens, Greece

    Fragiska Sigala

  5. Department of Anatomy, School of Medicine, University of Athens, Athens, Greece

    Elizabeth Johnson

  6. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens, Greece

    Andreas Scorilas

Authors
  1. Eirini Thanopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Kotzamanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ioannis S. Pateras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicholaos Ziras
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandros Papalambros
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Theodoros Mariolis-Sapsakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fragiska Sigala
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elizabeth Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Athanassios Kotsinas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andreas Scorilas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vassilis G. Gorgoulis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vassilis G. Gorgoulis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thanopoulou, E., Kotzamanis, G., Pateras, I.S. et al. The single nucleotide polymorphism g.1548A >G (K469E) of the ICAM-1 gene is associated with worse prognosis in non-small cell lung cancer. Tumor Biol. 33, 1429–1436 (2012). https://doi.org/10.1007/s13277-012-0393-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-012-0393-4

Keywords

Search

Navigation