Lioni Mercedes, Brafford Patricia, Andl Claudia, Rustgi Anil, El-Deiry Wafik, Herlyn Meenhard, Smalley Keiran S M
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA.
Am J Pathol. 2007 Feb;170(2):709-21. doi: 10.2353/ajpath.2007.060343.
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.
闭合蛋白构成了一个由24种蛋白质组成的家族，这些蛋白质对于紧密连接的功能和形成至关重要。在此，我们研究了闭合蛋白-7在食管鳞状细胞癌（SCC）中的表达及其在肿瘤进展中的可能作用。在正常食管中，闭合蛋白-7的表达局限于分化的角质形成细胞的细胞膜。然而，在肿瘤样本中，闭合蛋白-7的表达常常缺失或定位于细胞质。对食管SCC细胞系的检测显示闭合蛋白-7表达各异，有些细胞系完全缺乏其表达。使用小干扰RNA方法敲低SCC细胞系中的闭合蛋白-7导致E-钙黏蛋白表达降低、细胞生长增加以及对三维基质的侵袭增强。当在既缺乏闭合蛋白-7又缺乏E-钙黏蛋白的食管SCC细胞中过表达闭合蛋白-7时，观察到了相反的结果。在这种情况下，过表达闭合蛋白-7的细胞变得更具黏附性且侵袭性降低，同时E-钙黏蛋白表达增加。总之，我们证明了在食管角质形成细胞的恶性转化过程中闭合蛋白-7发生了定位错误。我们还证明了闭合蛋白-7表达在这些细胞中对E-钙黏蛋白的调节中起关键作用，这表明这可能是食管SCC中观察到的上皮结构丧失和侵袭的一种机制。
