Annals of Surgical Oncology

, Volume 16, Issue 9, pp 2486–2493 | Cite as

Reduced Axin Protein Expression Is Associated with a Poor Prognosis in Patients with Squamous Cell Carcinoma of Esophagus

  • Anna Fen-Yau Li
  • Po-Kuei Hsu
  • Ching Tzao
  • Yi-Ching Wang
  • I-Chun Hung
  • Min-Hsiung Huang
  • Han-Shui Hsu
Thoracic Oncology

Abstract

Aims

Our study investigates the significance of the expression of Wnt pathway proteins including β-catenin, Axin, β-transducin-repeat-containing protein (β-TrCP), and adenomatous polyposis coli (APC) in squamous cell carcinoma of the esophagus (ESCC).

Methods

Immunohistochemical analysis was performed on paraffin-embedded tissue specimens from 128 resected ESCC tumors to detect the expression of β-catenin, Axin, β-TrCP, and APC. Correlation between immunoexpression, clinicopathological parameters, and patient survival was analyzed.

Results

Increased β-catenin expression was noted in 22 (18.2%) of 121 tumor specimens. Reduced expression of Axin, β-TrCP, and APC was observed in 57 (46.0%) of 124, 29 (24.4%) of 119, and 54 (48.2%) of 119 specimens, respectively. No correlation was found among these protein expressions. Axin protein expression was inversely correlated with tumor invasion depth (P = 0.033). Reduced Axin protein expression, lymph node involvement, and distant metastasis were significant negative predictors for overall survival and disease-free survival on univariate analysis. In multivariate analysis, reduced Axin expression remained a significant prognostic factor for patients with ESCC (P = 0.005).

Conclusions

Reduced Axin expression was observed in 46% of ESCC tumor specimens and was associated with poor prognosis in patients with ESCC. Further study is mandatory to elucidate the underlying mechanism responsible for loss of Axin expression and the role of Axin in ESCC tumorigenesis.

Keywords

Esophageal Squamous Cell Carcinoma Adenomatous Polyposis Coli Esophageal Squamous Cell Carcinoma Cell Adenomatous Polyposis Coli Gene Adenomatous Polyposis Coli Protein 

References

  1. 1.
    Fahn HJ, Wang LS, Huang BS, et al. Tumor recurrence in long-term survivors after treatment of carcinoma of the esophagus. Ann Thorac Surg. 1994;57:677–81.PubMedGoogle Scholar
  2. 2.
    Ilyas M, Tomlinson IP, Rowan A, et al. Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci USA. 1997;16:10330–4.CrossRefGoogle Scholar
  3. 3.
    Clements WM, Wang J, Sarnaik A, et al. Beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002;15:3503–6.Google Scholar
  4. 4.
    Doucas H, Garcea G, Neal CP, et al. Changes in the Wnt signaling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer. 2005;41:365–79.PubMedCrossRefGoogle Scholar
  5. 5.
    Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99–109.PubMedCrossRefGoogle Scholar
  6. 6.
    Van Ooyen A, Nusse R. Structure and nucleotide sequence of the putative mammary oncogene Int-1; Proviral insertions leave the protein-encoding domain intact. Cell. 1984;39:233–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Nusse R, van Ooyen A, Cox D, et al. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature. 1984;307:131–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Rijsewijk F, Schuermann M, Wagenaar E, et al. The drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987;50:649–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Tsukamoto AS, Grossched R, Guzman RC, et al. expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell. 1988;55:619–25.PubMedCrossRefGoogle Scholar
  10. 10.
    Moon RT, Kohn AD, De Ferrari GV, et al. WNT and β-catenin signaling: disease and therapies. Nat Rev Genet. 2004;5:691–701.PubMedCrossRefGoogle Scholar
  11. 11.
    Ilyas M. Wnt signalling and the mechanistic basis of tumour development. J Pathol. 2005;205:130–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Logan CY, Nusse R. The WNT signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.PubMedCrossRefGoogle Scholar
  13. 13.
    Lustig B, Behrens J. The Wnt siganlling pathway and its role in tumor development. J Cancer Res Clin Oncol. 2003;129:199–221.PubMedGoogle Scholar
  14. 14.
    Nakajima M, Fukuchi M, Miyazaki T, et al. Reduced expression of Axin correlates with tumor progression of esophageal squamous cell carcinoma. Br J Cancer. 2003;88:1734–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual, 6th ed. New York: Springer-Verlag; 2002.Google Scholar
  16. 16.
    Kim YT, Park JY, Jeon YK, et al. Aberrant promoter CpG island hypermethylation of the adenomatosis polyposis coli gene can serve as a good prognostic factor by affecting lymph node metastasis in squamous cell carcinoma of the esophagus. Dis Esophagus. 2009;22:143–50.PubMedCrossRefGoogle Scholar
  17. 17.
    de Castro J, Gamallo C, Palacios J, et al. β-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcome. Virchows Arch. 2000;437:599–604.PubMedCrossRefGoogle Scholar
  18. 18.
    Kimura Y, Shiozaki H, Doki Y, et al. Cytoplasmic β-catenin in esophageal cancers. Int J Cancer. 1999;84:174–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Shiozaki H, Doki Y, Kawanishi K, et al. Clinical application of malignancy potential grading as a prognostic factor of human esophageal cancers. Surgery. 2000;127:552–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang G, Zhou X. Xue L, et al. Accumulation of cytoplasmic β-catenin correlates with reduced expression of E-cadherin, but not with phosphorylated Akt in esophageal squamous cell carcinoma: immunohistochemical study. Pathol Int. 2005;55:310–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Salahshor S, Woodgett JR. The links between Axin and carcinogenesis. J Clin Pathol. 2005;58:225–36.PubMedCrossRefGoogle Scholar
  22. 22.
    Jin LH, Shao QJ, Luo W, et al. Detection of point mutations of the Axin1 gene in colorectal cancers. Int J Cancer. 2003;107:696–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Satoh S, Diago Y, Furukawa Y, et al. Axin1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of Axin1. Nat Genet. 2000;24:245–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Xu HT, Wang L, Lin D, et al. Abnormal beta-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer. Am J Clin Pathol. 2006;125:534–41.PubMedGoogle Scholar
  25. 25.
    Yeh KT, Chang JG, Lin TH, et al. Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer. Int J Oncol. 2003;23:1001–7.PubMedGoogle Scholar
  26. 26.
    Jin LH, Shao QJ, Luo W, et al. detection of point mutations of the axin1 gene in colorectal cancers. Int J Cancer. 2003;107:696–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Baeza N, Masuoka J, Kleihues P, et al. Axin1 mutations but not deletions in cerebellar medulloblastomas. Oncogene. 2003;22:632–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Koppert LB, van der Velden AW, van de Wetering M, et al. Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-esophageal junction with nuclear β-catenin expression. Br J Cancer. 2004;90:892–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Wagata T, Ishizaki K, Imamura M, et al. Deletion of 17p and amplification of the int-2 gene in esophageal carcinomas. Cancer Res. 1991;51:2113–7.PubMedGoogle Scholar
  30. 30.
    Kudo J, Nishiwaki T, Haruki N, et al. Aberrant nuclear localization of β-catenin without genetic alternation in β-catenin or Axin genes in esophageal cancer. World J Surg Oncol. 2007;5:21–9.PubMedCrossRefGoogle Scholar
  31. 31.
    He N, Li C, Zhang X, et al. Regulation of lung cancer cell growth and invasiveness by beta-TRCP. Mol Carcinog. 2005;42:18–28.PubMedCrossRefGoogle Scholar
  32. 32.
    Furuhashi M, Yagi K, Yamamoto H, et al. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol. 2001;21:5132–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang Y, Neo SY, Wang X, et al. Axin forms a complex with MEKK1 and activates c-Jun NH(2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling. J Biol Chem. 1999;274:35247–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Neo SY, Zhang Y, Yaw LP, et al. Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels. Biochem Biophys Res Commun. 2000;272:144–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Ougolkov A, Zhang B, Yamashita K, et al. Associations among β-TrCP, an E3 ubiquitin ligase receptor, β-catenin, and NF-kB in colorectal cancer. J Natl Cancer Inst. 2004;96:1161–70.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2009

Authors and Affiliations

  • Anna Fen-Yau Li
    • 1
  • Po-Kuei Hsu
    • 2
  • Ching Tzao
    • 3
  • Yi-Ching Wang
    • 4
  • I-Chun Hung
    • 2
  • Min-Hsiung Huang
    • 2
  • Han-Shui Hsu
    • 2
    • 5
  1. 1.Department of PathologyTaipei Veterans General HospitalTaipeiTaiwan
  2. 2.Division of Thoracic Surgery, Department of SurgeryTaipei Veterans General HospitalTaipeiTaiwan
  3. 3.Division of Thoracic Surgery, Department of SurgeryTri-Service General HospitalTaipeiTaiwan
  4. 4.Department of Pharmacology, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  5. 5.Institute of Emergency and Critical Care MedicineNational Yang-Ming University School of MedicineTaipeiTaiwan

Personalised recommendations