Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas

Neoplasia. 2008 Jun;10(6):563-72. doi: 10.1593/neo.08208.


Tissue inhibitor of metalloproteinase 3 (TIMP-3) promoter methylation has been linked to loss of TIMP-3 expression in various cancers. In this study, we analyzed TIMP-3 gene methylation using MethyLight assay and TIMP-3 mRNA expression using reverse transcription-polymerase chain reaction analysis in 22 esophageal cancers, 27 gastric carcinomas, and 7 cancer cell lines. We also analyzed TIMP-3 protein expression by immunohistochemistry and its association with clinicopathological characteristics in two cohorts of gastric cancer comprising a total of 347 patients. The TIMP-3 gene was more commonly methylated in adenocarcinomas of the esophagus (9/13) and stomach (9/15) than in the corresponding nonneoplastic mucosa of the esophagus (1/8; P = .024) and stomach (2/14; P = .021). In gastric cancer patients, TIMP-3 was decreased in a diffuse-type gastric cancer and in cancers with poor differentiation and was associated with poor survival (P = .04). In summary, we observed frequent TIMP-3 promoter methylation in adenocarcinomas of the esophagus and stomach and the loss of TIMP-3 expression seems to be of clinical and prognostic relevance in these cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Line, Tumor
  • Cohort Studies
  • DNA Methylation
  • Disease Progression
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry / methods
  • Middle Aged
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology*
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*
  • Tissue Inhibitor of Metalloproteinase-3 / physiology*


  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3