Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer
Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer
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DOI：
10.1172/jci24543
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发表时间：
2005-07-01
影响因子：
15.9
通讯作者：
Beauchamp, RD
中科院分区：
文献类型：
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作者：
Dhawan, P;Singh, AB;Beauchamp, RD
细胞-细胞连接中断伴随着连接蛋白表达的改变是癌细胞侵袭和转移的标志。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(TJ)的作用了解较少。Claudius是新近发现的TJs结构和功能所必需的Tetraspanin家族成员。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；然而，Claudin的表达/定位与癌症之间的因果关系尚未建立。在这里，我们报告了Claudin-1在人类原发结肠癌和转移瘤中的表达增加，以及在原发和转移性肿瘤中的细胞细小颗粒中的表达。我们还报告了在这些样本中Claudin-1的频繁核定位。在结肠癌细胞系中表达claudin-1的基因操作导致了细胞表型的变化，伴随着上皮-间充质转化标志物的结构和功能的变化。此外，我们还证明了claudin-1表达的变化对裸鼠移植瘤的生长和转移有显著影响。我们进一步提供的数据表明，E-钙粘蛋白表达和β-连环蛋白/Tcf信号的调节可能是Claudin-1依赖变化的一个可能机制。
Disruption of the cell-cell junction with concomitant changes in the expression of junctional proteins is a hallmark of cancer cell invasion and metastasis. The role of adherent junction proteins has been studied extensively in cancer, but the roles of tight junction (TJ) proteins are less well understood. Claudius are recently identified members of the tetraspanin family of proteins, which are integral to the structure and function of TJs. Recent studies show changes in expression/cellular localization of claudins during tumorigenesis; however, a causal relationship between claudin expression/localization and cancer has not been established. Here, we report an increased expression of claudin-1 in human primary colon carcinoma and metastasis and in cell fines derived from primary and metastatic tumors. We also report frequent nuclear localization of claudin-1 in these samples. Genetic manipulations of claudin-1 expression in colon cancer cell lines induced changes in cellular phenotype, with structural and functional changes in markers of epithelial-mesenchymal transition. Furthermore, we demonstrate that changes in claudin-1 expression have significant effects on growth of xenografted tumors and metastasis in athymic mice. We further provide data suggesting that the regulation of E-cadherin expression and beta-catenin/Tcf signaling is a possible mechanism underlying claudin-1-dependent changes.