Role of claudin-1 in colon tumor progression and metastasis

描述（由申请人提供）：细胞-细胞连接的破坏伴随着连接蛋白表达的变化是癌症转移和侵袭的标志。粘附连接蛋白在癌症中的作用已被广泛研究，然而紧密连接蛋白的作用知之甚少。紧密连接蛋白是最近发现的四跨膜蛋白，其与紧密连接（TJ）的结构和功能不可或缺。最近的研究表明，在肿瘤发生过程中的表达/细胞定位的claudins的变化，但因果关系尚未建立。在这里，我们报告了一个高度增加的表达密蛋白-1在人类原发性结肠癌和转移性组织和细胞系来自类似的来源，相对频繁的核定位。此外，使用在结肠癌细胞系中的claudin-1表达的遗传操作，我们证明了claudin-1在调节上皮向间质转化（EMT）、异种移植肿瘤的生长和无胸腺小鼠中的转移中的作用。我们进一步显示调节E-钙粘蛋白的表达和？catenin/Tcf信号传导作为claudin-1依赖性EMT的可能机制。

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.