Overexpression of Claudin Proteins in Esophageal Adenocarcinoma and Its Precursor Lesions

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 non-dysplastic 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.

Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia

“…16 Among various genetic events a disturbed balance of TJ proteins, which regulate tissue integrity and paracellular transport, is believed to promote the development of BC. [17][18][19] In line with this hypothesis complex alterations of TJ expression in BE and BC compared to esophageal squamous epithelium have been observed: claudin-1 and claudin-5 are downregulated in BE 19,20 whereas for claudin-2, -3, -4 and -7 an upregulation has been noted, in particular in highgrade IN and BC. 17,19,21 These data suggest that downregulated TJ proteins might facilitate inhibitory functions, whereas upregulated TJs may promote the progression of BE.…”

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

“…This accounts for claudin-7 in breast (53,54) and esophageal cancer (55). However, up-regulated claudin-7 expression was seen in renal (56), cervical (57), and gastric cancer (58,59). This may be a consequence of claudin-7 being not only located in tight junctions, but also at the basolateral membrane and/or in vesicles (7,(60)(61)(62).…”

Decreased expression of claudin-1 is correlated with recurrence status in esophageal squamous cell carcinoma

“…In addition, there was a tendency to reduced the claudin-1 expression in the cases with venous clarified in the esophagus extensively. In addition, only several studies examined claudins expression in the esophageal diseases including cancers (6,13,15,23,28). In this study, we demonstrated that decreased expression of claudin-1 was correlated with the recurrence status in esophageal squamous cell carcinoma, and associated with short disease-free survival and overall survival.…”

“…The claudins have been suggested to be associated with carcinogenesis and tumor progression. Alteration of claudins has been detected in carcinomas of the esophagus (6,13,15,23,28), colorectum (14,19), and other cancers (16,21,24), suggesting that the claudins are involved in the process of carcinogenesis (20).…”