Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas.
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.
Department of Medicine II, Klinikum rechts der Isar, Technical University, Munich, Germany. Matthias.Ebert@lrz.tum.de
Ping
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Gu
Xiangbin
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Xing
Marc
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Tänzer
Christoph
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Röcken
Wilko
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Weichert
Audrius
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Ivanauskas
Matthias
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Pross
Ulrich
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Peitz
Peter
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Malfertheiner
Roland M
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Schmid
Matthias P A
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Ebert
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000502:physiology*
C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3