Low expression of claudin-4 is associated with poor prognosis in esophageal squamous cell carcinoma

Ann Surg Oncol. 2011 Jan;18(1):273-81. doi: 10.1245/s10434-010-1289-4. Epub 2010 Sep 14.


Background: Claudins are 22-27 kDa sized adhesion molecules that constitute tight junctions. Their expression levels are often tissue-specific, and their altered degrees of expression have been reported in a variety of cancers. In addition, the prognostic significance of claudin expression has been implicated in various human cancers. However, the prognostic significance of claudin-4 expression in esophageal squamous cell carcinoma (ESCC) remains to be clarified.

Materials and methods: We investigated the prognostic significance of claudin-4 expression in 164 cases of ESCC using immunohistochemisty. We also evaluated claudin-4 mRNA expression levels using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and analyzed its specific promoter methylation status using quantitative methylation-specific PCR.

Results: According to clinicopathological parameters, low claudin-4 expression was found to be significantly associated with histological differentiation (P = 0.003), invasion depth (P = 0.002), and lymph node metastasis (P = 0.024). Low claudin-4 expression showed unfavorable influences on disease-free survival (P = 0.0115) and overall survival (OS) (P = 0.0009). In multivariate analysis, low claudin-4 expression was an independent predictor of poor OS (P = 0.007). Claudin-4 mRNA levels assessed using real-time RT-PCR were consistent with the protein levels determined using immunohistochemistry. Furthermore, this study demonstrates that loss of claudin-4 is associated with promoter hypermethylation.

Conclusions: Our study indicates that claudin-4 expression is deregulated in ESCC, implying its potential use as a prognostic biomarker in ESCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Claudin-4
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophagus / metabolism*
  • Esophagus / pathology
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Lymphatic Metastasis
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Microdissection
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tissue Array Analysis


  • Biomarkers, Tumor
  • CLDN4 protein, human
  • Claudin-4
  • DNA, Neoplasm
  • Membrane Proteins
  • RNA, Messenger