Dysregulation of claudin-7 leads to loss of E-cadherin expression and the increased invasion of esophageal squamous cell carcinoma cells.
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.
Lioni
Mercedes
M
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA.
Brafford
Patricia
P
Andl
Claudia
C
Rustgi
Anil
A
El-Deiry
Wafik
W
Herlyn
Meenhard
M
Smalley
Keiran S M
KS
D015820:Cadherins / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D057167:Claudins; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering / Q000096:biosynthesis* / Q000494:pharmacology
C473255:CLDN7 protein, human; D015820:Cadherins; D057167:Claudins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering