Overexpression of Claudin proteins in esophageal adenocarcinoma and its precursor lesions

Elizabeth Montgomery, Adam J. Mamelak, Michael Gibson, Anirban Maitra, Salwa Sheikh, Samir S. Amr, Stephen Yang, Malcolm Brock, Arlene Forastiere, Shengle Zhang, Kathleen M. Murphy, Karin D. Berg

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Claudins are components of tight junctions important in intercellular barriers and cell polarity. The authors identified upregulation of Claudins 3, 4, and 7 in gastric adenocarcinoma using Affymetrix U-133 oligonucleotide microarrays and immunohistochemistry (IHC). While normal gastric mucosa lacked Claudin 3, 4, and 7 expression, intestinal metaplasia and dysplasia showed these proteins. The authors hypothesized that Claudins would be similarly overexpressed in Barrett's esophagus (BE)/adenocarcinoma. Claudins 3, 4, and 7 gene expression was analyzed by Affymetrix U-133 microarrays in three esophageal adenocarcinomas, one case of BE, and three normal esophagi. IHC validation was performed using tissue microarrays constructed from esophageal resection specimens containing squamous (44 cases), gastric (40 cases), and nondysplastic BE (16 cases), low-grade and high-grade dysplasia (16 and 26 cases), adenocarcinoma (58 cases), and nodal metastases (27 cases). IHC staining was scored semiquantitatively (0+ to 4+). By microarray analysis, Claudin 3 showed a marked increase in mRNA expression compared with normal esophagus (approximately 100-fold). Claudins 4 and 7 were modestly increased (2.2- and 1.3-fold). By IHC, Claudin 3 expression was 1+ in most (> 95%) normal squamous or gastric tissues and 2+ to 4+ in more than 80% of high-grade dysplasia, adenocarcinoma, and metastases specimens. Claudin 4 protein expression was 2+ or less in most squamous and gastric mucosa (> 90%) but 3+ or 4+ in BE, low- and high-grade dysplasia, adenocarcinoma, and metastases specimens (> 90%). Claudin 7 expression was minimal in squamous and gastric mucosa but strong (3+ to 4+) in BE and low-grade dysplasia. In high-grade dysplasia, adenocarcinoma, and metastases, Claudin 7 was less intense, with 60% to 70% staining 3+ or 4+ and 30% to 40% staining weakly (1+ or 2+). The findings suggest that alterations in Claudin proteins are an early event in tumorigenesis and may provide targets for diagnosis and directed therapy for esophageal adenocarcinoma and its precursors.

Original languageEnglish (US)
Pages (from-to)24-30
Number of pages7
JournalApplied Immunohistochemistry and Molecular Morphology
Volume14
Issue number1
DOIs
StatePublished - Mar 2006
Externally publishedYes

Keywords

  • Adenocarcinoma
  • Barrett's esophagus
  • Dysplasia
  • Gene expression
  • Intestinal metaplasia

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Medical Laboratory Technology

Fingerprint

Dive into the research topics of 'Overexpression of Claudin proteins in esophageal adenocarcinoma and its precursor lesions'. Together they form a unique fingerprint.

Cite this