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改变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，而紧密连接蛋白的作用尚不清楚。Claudins是最近发现的四联蛋白，是紧密连接（TJs）结构和功能的组成部分。最近的研究表明，在肿瘤发生过程中，claudin的表达/细胞定位发生了变化，但尚未建立因果关系。在这里，我们报道了claudin-1在人类原发性结肠癌和转移性组织和细胞系中高度增加的表达，这些组织和细胞系来源于相对频繁的核定位。此外，通过对结肠癌细胞系中claudin-1表达的基因操作，我们证实了claudin-1在胸腺小鼠中调控上皮细胞向间质转化（EMT）、异种移植肿瘤的生长和转移中的作用。我们进一步发现E-cadherin和？-catenin/Tcf信号作为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.