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Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance

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Tumor Biology

Abstract

Activation of the wingless-type (Wnt) signaling pathway is common in various human cancers including colorectal cancer (CRC). Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind Wnt ligands and therefore inhibits the Wnt signaling pathway. In this study, we aimed to analyze the expression of two members of Wnt signaling (WIF-1 and Wnt5a) in Tunisian patients with sporadic CRC. WIF-1 was frequently methylated in tumor tissues (87.95 %) compared to normal mucosa (39.54 %) and correlated with distant metastasis and vascular invasion (P = 0.001 and 0.037, respectively). The unmethylated profile of the WIF-1 promoter conferred a benefit to patients in terms of overall survival (P log rank = 0.024). In addition, in the group of patients with methylated WIF-1 promoter, the overall survival rate was significantly prolonged for those with small tumor size (<5 cm) and absence of distant metastasis (P log rank = 0.007 and 0.036, respectively). Aberrant CpG methylation of the WIF-1 promoter leads to transcriptional silencing of this tumor suppressor gene in tumor tissues (P = 0.001). Furthermore, we showed that the level of Wnt5a mRNA was significantly lower in tumor compared to normal tissues (P = 0.031) and lower still in those showing more aggressive behavior (presence of lymph nodes and advanced TNM stage). Our finding supports that WIF-1 is frequently methylated and that Wnt5a acts as a tumor suppressor gene in CRC. Loss of WIF-1 and Wnt5a functions results in more aggressive behavior of the disease.

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References

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

    Article  PubMed  Google Scholar 

  2. Hsairi M, Fakhfakh R, Ben Abdallah M, Jlidi R, Sellami A, Zheni S, et al. Assessment of cancer in Tunisia. Tunis Med. 2002;80:57–64.

    PubMed  Google Scholar 

  3. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin. 2006;56:11–25.

    Article  PubMed  Google Scholar 

  4. Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000;119:854–65.

    Article  CAS  PubMed  Google Scholar 

  5. Baylin SB, Ohm JE. Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction. Nat Rev Cancer. 2006;6:107–11.

    Article  CAS  PubMed  Google Scholar 

  6. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623–7.

    Article  CAS  PubMed  Google Scholar 

  7. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96:8681–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Med. 2004;23:29–39.

    CAS  Google Scholar 

  9. Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4:988–93.

    Article  CAS  PubMed  Google Scholar 

  10. Xu XL, Yu J, Zhang HY, Sun MH, Gu J, Du X, et al. Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. World J Gastroenterol. 2004;10:3441–54.

    CAS  PubMed  Google Scholar 

  11. Miladi-Abdennadher I, Abdelmaksoud-Damak R, Ayadi L, Khabir A, Amouri A, Frikha F, et al. Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma. Biosci Rep. 2011;31(4):257–64.

    Article  CAS  PubMed  Google Scholar 

  12. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.

    CAS  PubMed  Google Scholar 

  13. Shimizu Y, Ikeda S, Fujimori M, Kodama S, Nakahara M, Okajima M, et al. Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability. Genes Chromosome Cancer. 2002;3(1):73–8.

    Article  Google Scholar 

  14. Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006;25(57):7531–7.

    Article  CAS  PubMed  Google Scholar 

  15. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286–330.

    Article  CAS  PubMed  Google Scholar 

  16. Suzuki H, Toyota M, Carraway H, Gabrielson E, Ohmura T, Fujikane T, et al. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. Br J Cancer. 2008;98:1147–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell. 2002;1:279–88.

    Article  CAS  PubMed  Google Scholar 

  18. Uematsu K, He B, You L, Xu Z, McCormick F, Jablons DM. Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene. 2003;22:7218–21.

    Article  CAS  PubMed  Google Scholar 

  19. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:3118–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Fendri A, Khabir A, Hadri-Guiga B, Sellami-Boudawara T, Daoud J, Frikha M, et al. Epigenetic alteration of the Wnt inhibitory factor-1 promoter is common and occurs in advanced stage of Tunisian nasopharyngeal carcinoma. Cancer Invest. 2010;28:896–903.

    Article  CAS  PubMed  Google Scholar 

  21. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.

    Article  CAS  PubMed  Google Scholar 

  22. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36:417–22.

    Article  CAS  PubMed  Google Scholar 

  23. Aguilera O, Fraga MF, Paz BEMF, Herranz M, Espada J, García JM, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25:4116–21.

    Article  CAS  PubMed  Google Scholar 

  24. Slusarski DC, Yang-Snyder J, Busa WB, Moon RT. Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A. Dev Biol. 1997;182:114–20.

    Article  CAS  PubMed  Google Scholar 

  25. Umbhauer M, Djiane A, Goisset C, Penzo-Méndez A, Riou JF, Boucaut JC, et al. The C-terminal cytoplasmic Lys-thr-X-X-X-Trp motif in frizzled receptors mediates Wnt/beta-catenin signalling. EMBO J. 2000;19:4944–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Huang C-L, Liu D, Nakano J, Ishikawa S, Kontani K, Yokomise H, et al. Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor: an expression in non-small-cell lung cancer. J Clin Oncol. 2005;23:8765–73.

    Article  PubMed  Google Scholar 

  27. Lejeune S, Huguet EL, Hamby A, Poulsom R, Harris AL. Wnt5a cloning, expression, and up-regulation in human primary breast cancers. Clin Cancer Res. 1995;1:215–22.

    CAS  PubMed  Google Scholar 

  28. Blanc E, Roux GL, Bénard J, Raguénez G. Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Oncogene. 2005;24:1277–83.

    Article  CAS  PubMed  Google Scholar 

  29. Kremenevskaja N, von Wasielewski R, Rao AS, Schöfl C, Andersson T, Brabant G. Wnt 5a has tumor suppressor activity in thyroid carcinoma. Oncogene. 2005;24:2144–54.

    Article  CAS  PubMed  Google Scholar 

  30. Dejmek J, Dejmek A, Safholm A, Sjolander A, Andersson T. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res. 2005;65(20):9142–6.

    Article  CAS  PubMed  Google Scholar 

  31. Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH. Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch. 2009;455(6):485–94.

    Article  CAS  PubMed  Google Scholar 

  32. Ying J, Li H, Yu Ju Ng KM, Poon FF, Wong SC, et al. WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/b-Catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res. 2008;14:55–61.

    Article  CAS  PubMed  Google Scholar 

  33. Li Q, Chen H. Silencing of Wnt5a during colon cancer metastasis involves histone modifications. Epigenetics. 2012;7(6):551–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Bauer M, Bénard J, Gaasterland T, Willert K, Cappellen D. WNT5A encodes two isoforms with distinct functions in cancers. PLoS One. 2013;18:8(11).

    Google Scholar 

  35. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–9.

    Article  CAS  PubMed  Google Scholar 

  37. Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002;30:e36.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT. The Wnt/Ca2+ pathway: a new vertebrate Wnt signalling pathway takes shape. Trends Genet. 2000;16:279–83.

    Article  CAS  PubMed  Google Scholar 

  39. Taniguchi H, Yamamoto H, Hirata T, Miyamoto N, Oki M, Nosho K, et al. Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. Oncogene. 2005;24:7946–52.

    Article  CAS  PubMed  Google Scholar 

  40. Maehata T, Taniguchi H, Yamamoto H, Nosho K, Adachi Y, Miyamoto N, et al. Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer. World J Gastroenterol. 2008;14:2702–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Lee BB, Lee EJ, Jung EH, Chun HK, Chang DK, Song SY, et al. Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res. 2009;15:6185–91.

    Article  CAS  PubMed  Google Scholar 

  42. Ai L, Tao Q, Zhong S, Fields CR, Kim W-J, Lee MW, et al. Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis. 2006;27:1341–8.

    Article  CAS  PubMed  Google Scholar 

  43. Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, et al. Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 2004;64:4717–20.

    Article  CAS  PubMed  Google Scholar 

  44. Rawson JB, Mrkonjic M, Daftary D, Dicks E, Buchanan DD, Younghusband HB, et al. Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br J Cancer. 2011;104(12):1906–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Roarty K, Baxley SE, Crowley MR, Frost AR, Serra R. Loss of TGF-beta or Wnt5a results in an increase in Wnt/beta-catenin activity and redirects mammary tumour phenotype. Breast Cancer Res. 2009;11:R19.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Trifa F, Karray-Chouayekh S, Jmal E Jmaa ZB, Khabir A, Sellami-Boudawara T, Frikha M, Daoud J, Mokdad-Gargouri R. Loss of WIF-1 and Wnt5a expression is related to aggressiveness of sporadic breast cancer in Tunisian patients. Tumor Biol. 2013

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Acknowledgments

This work was supported by a grant of the Tunisian Ministry of High Education and Scientific Research.

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Authors and Affiliations

  1. Laboratory of Biomass Valorisation and Production of Eukaryotic Proteins, Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour street, BP“K”1177, 3018, Sfax, Tunisia

    Rania Abdelmaksoud-Dammak, Imen Miladi-Abdennadher, Amena Saadallah-Kallel & Raja Mokdad-Gargouri

  2. Centre Hospitalo-Universitaire Habib Bourguiba, 3000, Sfax, Tunisia

    Abdelmajid Khabir, Tahia Sellami-Boudawara, Mounir Frikha & Jamel Daoud

  3. Centre de Biotechnologie de Sfax, Sidi Mansour Street, BP K 1177, 3018, Sfax, Tunisia

    Raja Mokdad-Gargouri

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  1. Rania Abdelmaksoud-Dammak
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Correspondence to Raja Mokdad-Gargouri.

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Abdelmaksoud-Dammak, R., Miladi-Abdennadher, I., Saadallah-Kallel, A. et al. Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance. Tumor Biol. 35, 7975–7982 (2014). https://doi.org/10.1007/s13277-014-2015-9

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  • DOI: https://doi.org/10.1007/s13277-014-2015-9

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