Role of claudin-1 in colon tumor progression and metastasis

描述(由申请人提供)：细胞-细胞连接中断伴随连接蛋白表达的变化是癌症转移和侵袭的标志。黏附连接蛋白在癌症中的作用已被广泛研究，但对紧密连接蛋白的作用知之甚少。克劳丁是新近发现的与紧密连接(TJ)结构和功能密切相关的四肽类化合物。最近的研究表明，在肿瘤发生过程中，Claudins的表达/细胞定位发生了变化，但因果关系尚未建立。在这里，我们报告了Claudin-1在人类原发结肠癌和转移性组织中的高度表达，以及来自具有相对频繁核定位的相似来源的细胞系。此外，通过对结肠癌细胞系中claudin-1表达的基因操作，我们证明了claudin-1在无瘤小鼠上皮向间充质转化(EMT)、异种移植瘤生长和转移中的调节作用。我们进一步表明，调节E-钙粘蛋白的表达和β-连环蛋白/Tcf信号通路可能是claudin-1依赖的EMT的一种可能机制。

DESCRIPTION (provided by applicant): Disruption of the cell-cell junction with concomitant changes in the expression of junctional proteins is a hallmark of cancer metastasis and invasion. Role of adherent junction proteins have been studied extensively in cancer, however the role of tight junction proteins is less understood. Claudins are the recently identified tetraspanins, which are integral to the structure and function of tight junctions (TJs). Recent studies have shown changes in expression/cellular localization for claudins during tumorigenesis, however a cause and effect relationship has not been established. Here, we report a highly increased expression for claudin-1 in human primary colon carcinoma and metastatic tissues and cell lines derived from similar sources with relatively frequent nuclear localization. Furthermore, using genetic manipulations of claudin-1 expression in colon cancer cell lines, we demonstrate a role for claudin-1 in the regulation of epithelial to mesenchymal transition (EMT), growth of xenografted tumors and metastasis in athymic mice. We further show regulation of E-cadherin expression and ?-catenin/Tcf signaling as a possible mechanism for claudin-1 dependent EMT.