Mol Cell Bio：紧密连接蛋白促进乳腺癌肝转移

紧密连接蛋白与恶性肿瘤的发生和发展有着密切关系，Claudin蛋白是细胞间的紧密连接蛋白的主要结构之一。Claudin蛋白目前研究较多，其中与恶性肿瘤相关的Claudin蛋白主要有7种，不同的肿瘤组织表达的Claudin类蛋白种类、量是不同的，在研究恶性肿瘤诊断、治疗的新手段方面，Claudin蛋白有很大前景。

早期研究确定蛋白紧密连接-2（claudin-2）是乳腺癌肝转移的重要功能性调解因子。近来Mol Cell Bio杂志刊登的一项研究发现肝转移患者中claudin-2的表达水平升高，但皮肤转移患者claudin-2不表达，这是根据乳腺癌患者相匹配的原发肿瘤类型而定的。

此外，与骨骼或肺转移的癌症患者群相比，claudin-2特异表达在肝脏转移性乳腺癌细胞中。此外，减少claudin-2的表达，无论是在肿瘤细胞或原代肝细胞中，都会抑制这些异型细胞与肝细胞之间的相互作用。

最后，研究表明，claudin-2的细胞外循环部位对介导肿瘤细胞/肝细胞相互作用以及乳腺癌细胞在体内形成肝转移的能力是必不可少的。因此，在乳腺癌肝转移过程中，claudin-2在乳腺癌细胞和肝细胞之间相关作用过程中从紧密连接复合体状态转变成粘附分子来发挥作用。

doi:10.1128/​MCB.00299-12
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Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes

Sébastien Tabariès, Fanny Dupuy, Zhifeng Dong, Anie Monast, Matthew G. Annis, et al.

We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2 expressing breast cancer cells requires claudin-2 mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, reducing claudin-2 expression, either in cancer cells or primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell/hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.