Advertisement

Tumor Biology

, Volume 32, Issue 1, pp 71–76 | Cite as

Analysis of β-catenin alterations in colon tumors: a novel exon 3 mutation

  • Elif Akisik
  • Dursun Buğra
  • Sumer Yamaner
  • Nejat Dalay
Research Article

Abstract

The great majority of colorectal cancers have defects in the Wnt signaling pathway indicating that this pathway has an important role in carcinogenesis. Alterations in the β-catenin gene are observed in 10–50% of the patients with colorectal cancer. Mutations of the β-catenin gene frequently occur in a region coding the protein phosphorylation domain harboring the Ser33/37/Thr41 and Ser45 sites and the inhibition of phosphorylation. Disruption of the β-catenin regulation plays a critical role in tumor development. In this study, we analyzed expression and mutations of β-catenin and phosphorylation of the Ser45 and Ser33/37/Thr41 residues in the tumors and matched normal tissue samples of patients with colorectal cancer. We did not observe significant differences in the phosphorylation rates between the patients and the control group. Samples displaying different levels of phosphorylation in the tumor and normal tissue were analyzed for exon 3 mutations of the β-catenin gene. In three of 57 patients, a novel G to A substitution was found at codon 15. This nucleotide change has not been reported previously in the literature. β-catenin protein levels and the degree of Ser45 or Ser33/37/Thr41 phosphorylation in tumor and normal tissue were not associated with the clinical parameters. Our results indicate that differences in the expression and phosphorylation of β-catenin are not very frequent in colon cancer, but mutations in exon 3 of the β-catenin gene may be responsible for a significant proportion of the tumors.

Keywords

Colorectal cancer β-catenin Tumor Phosphorylation 

Notes

Conflıcts of ınterest

The authors state that they have no conflicts of interest.

References

  1. 1.
    Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–70.CrossRefPubMedGoogle Scholar
  2. 2.
    Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–52.CrossRefPubMedGoogle Scholar
  3. 3.
    Behrens J, Lustig B. The Wnt connection to tumorigenesis. Int J Dev Biol. 2004;48:477–87.CrossRefPubMedGoogle Scholar
  4. 4.
    Capelluto DG, Kutateladze TG, Habas R, Finkielstein CV, He X, Overduin M. The DIX domain targets dishevelled to actin stress fibres and vesicular membranes. Nature. 2002;419:726–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Cong F, Schweizer L, Varmus H. Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP. Development. 2004;131:5103–15.CrossRefPubMedGoogle Scholar
  6. 6.
    Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev. 1996;59:3–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000;19:1839–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.PubMedGoogle Scholar
  9. 9.
    Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998;17:1371–84.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–47.CrossRefPubMedGoogle Scholar
  11. 11.
    Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 2002;16:1066–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/ β-Catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998;58:1130–4.PubMedGoogle Scholar
  13. 13.
    Gavert N, Ben-Zeev A. β-catenin signaling in biological control and cancer. J Cell Biol. 2007;102:820–4.Google Scholar
  14. 14.
    Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2:a002915.CrossRefPubMedGoogle Scholar
  15. 15.
    Yang J, Zhang W, Evans PM, Chen X, He X, Liu C. Adenomatous Polyposis Coli (APC) differantially regulates β-catenin phosphorylation and ubiquitination in colon cancer cells. J Biol Chem. 2006;281:17751–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Sadot E, Conacci-Sorrell M, Zhurinsky J, Shnizer D, Lando Z, Zharhary D, et al. Regulation of S33/S37 phosphorylated β-catenin in normal and transformed cells. J Cell Sci. 2002;115:2771–80.PubMedGoogle Scholar
  17. 17.
    Kitaeva MN, Grogan L, Williams JP, Dimond E, Nakahara K, Hausner P, et al. Mutations in β-catenin are uncommon in colorectal cancer occurring in occasional replication error-positive tumors. Cancer Res. 1997;57:4478–81.PubMedGoogle Scholar
  18. 18.
    Yu Z, Weinberger PM, Provost E, Haffty BG, Sasaki C, Joe J, et al. β-catenin functions mainly as an adhesion molecule in patients with squamous cell cancer of the head and neck. Clin Cancer Res. 2005;11:2471–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Abutaily AS, Collins JE, Roche WR. Cadherins, catenins and APC in pleural malignant mesothelioma. J Pathol. 2003;201:355–62.CrossRefPubMedGoogle Scholar
  20. 20.
    Behrens J. The role of the Wnt signaling pathway in colorectal tumorigenesis. Biochem Soc Trans. 2005;33:672–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Brembeck FH, Rosário M, Birchmeier. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr Opin Genet Dev. 2006;16:51–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Amary MFC, Pauwels P, Meulemans E, Roemen GM, Islam L, Idowu B, et al. Detection of β-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-spesific restriction enzyme digestion (MSRED): an ancillary diagnostic tool. Am J Surg Pathol. 2007;31:1299–309.CrossRefPubMedGoogle Scholar
  23. 23.
    Mikami M, Nosho K, Yamamoto H, Takahashi T, Maehata T, Taniguchi H, et al. Mutational analysis of β-catenin and the RAS-RAF signalling pathway in early flat-type colorectal tumours. Eur J Cancer. 2006;42:3065–72.CrossRefPubMedGoogle Scholar
  24. 24.
    Yamada Y, Oyama T, Hirose Y, Hara A, Sugie S, Yoshida K, et al. β-catenin mutations is selected during malignant trnsformation in colon carcinogenesis. Carcinogenesis. 2003;24:91–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Mittal K. The 9 lives of β-Catenin. J Human Pathol. 2004;35:647–8.CrossRefGoogle Scholar
  26. 26.
    Akiyama T. Wnt/ β-catenin signaling. Cytokine Growth Factor Rev. 2000;11:273–82.CrossRefPubMedGoogle Scholar
  27. 27.
    Provost E, McCabe A, Stern J, Lizardi I, D’Aquila TG, Rimm DL. Functional correlates of mutation of the Asp32 and Gly34 residues of β-catenin. Oncogene. 2005;24:2667–76.CrossRefPubMedGoogle Scholar
  28. 28.
    Xia J, Urabe K, Moroi Y, Koga T, Duan H, Li Y, et al. Beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas. J Dermatol Sci. 2006;42:67–75.CrossRefGoogle Scholar
  29. 29.
    Nilbert M, Rambech E. β-catenin activation through mutation is rare in rectal cancer. Cancer Genet Cytogenet. 2001;128:43–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Takayasu H, Motoi T, Kanamori Y, Kitano Y, Nakanishi H, Tange T, et al. Two case-reports of childhood liver-cell adenomas harboring β-catenin abnormalities. Hum Pathol. 2002;33:852–5.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • Elif Akisik
    • 1
  • Dursun Buğra
    • 2
  • Sumer Yamaner
    • 2
  • Nejat Dalay
    • 1
  1. 1.Department of Basic Oncology, Oncology InstituteIstanbul UniversityCapaTurkey
  2. 2.Department of Surgery, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

Personalised recommendations