Skip to main content

Advertisement

SpringerLink
Log in

WWOX gene may contribute to progression of non-small-cell lung cancer (NSCLC)

  • Research Article
  • Published:
Tumor Biology

Abstract

Lung cancer is the most common cause of cancer-related death worldwide and, like many other cancers, is affected by different genetic, epigenetic, and environmental factors. The WW domain-containing oxidoreductase (WWOX) gene is a tumor-suppressor gene located on chromosome 16q23.3–24.1, and it has been shown that it loses its function due to alterations in genetic and epigenetic mechanisms. The aim of this study is to investigate the relationship between lung cancer and WWOX gene. Tumor tissue samples, corresponding normal tissues, and blood samples obtained from 50 lung cancer patients were involved in the study. We analyzed methylation profile by methylation-specific PCR and mutations and polymorphisms by DNA sequencing. Methylation analysis showed that promoter hypermethylation was present in 38 of 50 (76%) patients. In addition, promoter region of WWOX gene of younger patients was more frequently methylated than older patients. Using DNA sequencing, we found four genetic alterations in WWOX gene. Two of them were germline mutations (Exon 4 and 7), and two of them were polymorphic (Exon 6 and 8). We found a new mutation in exon 7 (Arg-254→Cys) which has not been described previously. The changes in the short-chain dehydrogenase domain of the protein caused by the genetic alterations may affect the function of the gene. We conclude that hypermethylation of WWOX gene promoter region and mutations in the gene might be related to lung carcinogenesis.

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

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisami P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. La Vecchia C, Franceschi S, Levi F. Epidemiological research on cancer with a focus on Europe. Eur J Cancer Prev. 2003;12:5–14.

    Article  PubMed  Google Scholar 

  3. Peto R, Darby S, Deo H. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000;321:323–9.

    Article  CAS  PubMed  Google Scholar 

  4. Simonato L, Agudo A, Ahrens W. Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogenity. Int J Cancer. 2001;91:876–87.

    Article  CAS  PubMed  Google Scholar 

  5. Capewell S, Sankaran R, Lamb D. Lung cancer in lifelong non-smokers. Edinburgh Lung Cancer Group. Thorax. 1991;46:565–8.

    Article  CAS  PubMed  Google Scholar 

  6. Yunis JJ, Sarens AL, Bowe AE. Fragile sites are targets of diverse mutagens and carcinogens. Oncogene. 1987;1:59–69.

    CAS  PubMed  Google Scholar 

  7. Bednarek AK, Laflin KJ, Daniel RL, et al. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3–24.1, a region frequently affected in breast cancer. Cancer Res. 2000;60:2140–5.

    CAS  PubMed  Google Scholar 

  8. Ludes-Meyers JH, Bednarek AK, Popescu NC, et al. WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenet Genome Res. 2003;100:101–10.

    Article  CAS  PubMed  Google Scholar 

  9. Ludes-Meyers JH, Kil H, Bednarek AK, et al. WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins. Oncogene. 2004;23:5049–55.

    Article  CAS  PubMed  Google Scholar 

  10. Aqeilan RI, Pekarsky Y, Herrero JJ, et al. Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci. 2004;101:4401–6.

    Article  CAS  PubMed  Google Scholar 

  11. Aqeilan RI, Palamarchuk A, Weigel RJ, et al. Physical and functional interactions between the WWOX tumor suppressor protein and the AP-2λ transcription factor. Cancer Res. 2004;64:8256–61.

    Article  CAS  PubMed  Google Scholar 

  12. Aqeilan RI, Donati V, Palamarchuk A, et al. WW-domain containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res. 2005;65:6764–72.

    Article  CAS  PubMed  Google Scholar 

  13. Hezova R, Ehrmann J, Kolar Z. WWOX, a new potential tumor supressor gene. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007;151(1):11–5.

    CAS  PubMed  Google Scholar 

  14. Chang N-S, Doherty J, Ensign A. JNK1 physically interacts with WW-domain containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis. J Biol Chem. 2003;278:9195–202.

    Article  CAS  PubMed  Google Scholar 

  15. Wang X, Chao L, Jin G, et al. Association between CpG island methylation of the WWOX gene and its expression in breast cancers. Tumor Biol. 2009;30:8–14.

    Article  Google Scholar 

  16. Alsop AE, Taylor K, Zhang J, et al. Homozygous deletions may be markers of nearby heterozygous mutations.: the complex deletion at FRA16D in the colon cancer cell line removes exons of WWOX genes. Chromosomes & cancer. 2008;47:437–47.

    Article  CAS  Google Scholar 

  17. Aqeilan RI, Trapasso F, Hussain S, et al. Targeted deletions of WWOX reveals a tumor suppressor function. Proc Nat Acad Sci. 2007;104:3949–54.

    Article  CAS  PubMed  Google Scholar 

  18. Wang M, Gu J, Wang Y, et al. Loss of WWOX expression in human extrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol. 2008;135(1):39–44.

    Article  PubMed  Google Scholar 

  19. Kuroki T, Trapasso F, Shiraishi T, et al. Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res. 2002;62:2258–60.

    CAS  PubMed  Google Scholar 

  20. Herman JG, Graff JR, Myöhanen S, et al. Methylation-specific PCR: a novel PCR assay for metylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93:9821–6.

    Article  CAS  PubMed  Google Scholar 

  21. Yendamuri S, Kuroki T, Trapasso F, et al. WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. Cancer Res. 2003;63:878–81.

    CAS  PubMed  Google Scholar 

  22. Donati V, Fontanini G, Dell’Omodarme M, et al. WWOX expression in different histological types and subtypes of non-small cell lung cancer. Clin Cancer Res. 2007;13:884–91.

    Article  CAS  PubMed  Google Scholar 

  23. Paige AJ, Taylor KJ, Taylor C, et al. WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci USA. 2001;98:11417–22.

    Article  CAS  PubMed  Google Scholar 

  24. Pimenta F, Gomes DA, Perdigao PF, et al. Characterization of the tumor supressor gene WWOX in primary human oral squamous cell carcinomas. Int J Cancer. 2006;118:1154–8.

    Article  CAS  PubMed  Google Scholar 

  25. Kuroki T, Yendamuri S, Trapasso F, et al. The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin Cancer Res. 2004;10:2459–65.

    Article  CAS  PubMed  Google Scholar 

  26. Iliopoulos D, Guler G, Han SY, et al. Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene. 2005;24:1625–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The present work has been supported by the Research Fund of İstanbul University (project numbers T-7/15122006 and UDP-4219).

Author information

Authors and Affiliations

  1. Department of Medical Biology, Istanbul University Cerrahpasa Medical Faculty, Kat:6 Kocamustafapasa, Istanbul, Turkey

    Onur Baykara & Nur Buyru

  2. Department of Chest Surgery, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey

    Ahmet Demirkaya & Kamil Kaynak

  3. Department of Chest Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Serhan Tanju & Alper Toker

Authors
  1. Onur Baykara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmet Demirkaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kamil Kaynak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Serhan Tanju
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alper Toker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nur Buyru
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nur Buyru.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baykara, O., Demirkaya, A., Kaynak, K. et al. WWOX gene may contribute to progression of non-small-cell lung cancer (NSCLC). Tumor Biol. 31, 315–320 (2010). https://doi.org/10.1007/s13277-010-0039-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-010-0039-3

Keywords

Search

Navigation