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(American Journal of Pathology. 2007;170:709-721.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060343

Dysregulation of Claudin-7 Leads to Loss of E-Cadherin Expression and the Increased Invasion of Esophageal Squamous Cell Carcinoma Cells

Mercedes Lioni^*, Patricia Brafford^*, Claudia Andl, Anil Rustgi, Wafik El-Deiry, Meenhard Herlyn^* and Keiran S.M. Smalley^*

From The Wistar Institute,^* Philadelphia; and the Departments of Medicine and Genetics, Gastroenterology Division, and the Departments of Medicine and Genetics, Hematology-Oncology Division, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

The claudins constitute a 24-member family of proteins that are critical for the function and formation of tight junctions. Here, we examine the expression of claudin-7 in squamous cell carcinoma (SCC) of the esophagus and its possible role in tumor progression. In the normal esophagus, expression of claudin-7 was confined to the cell membrane of differentiated keratinocytes. However, in the tumor samples, claudin-7 expression is often lost or localized to the cytoplasm. Assaying esophageal SCC lines revealed variable expression of claudin-7, with some lacking expression completely. Knockdown of claudin-7 in SCC cell lines using a small interfering RNA approach led to decreased E-cadherin expression, increased cell growth, and enhanced invasion into a three-dimensional matrix. The opposite was observed when claudin-7 was overexpressed in esophageal SCC cells lacking both claudin-7 and E-cadherin. In this context, the claudin-7-overexpressing cells became more adhesive and less invasive associated with increased E-cadherin expression. In summary, we demonstrate that claudin-7 is mislocalized during the malignant transformation of esophageal keratinocytes. We also demonstrate a critical role for claudin-7 expression in the regulation of E-cadherin in these cells, suggesting this may be one mechanism for the loss of epithelial architecture and invasion observed in esophageal SCC.

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