Tenascin C Induces Epithelial-Mesenchymal Transition-Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells
Tenascin C Induces Epithelial-Mesenchymal Transition-Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells
复制标题
DOI：
10.1016/j.ajpath.2010.10.015
复制
发表时间：
2011-02-01
影响因子：
6
通讯作者：
Imanaka-Yoshida, Kyoko
中科院分区：
文献类型：
--
作者：
Nagaharu, Keiki;Zhang, Xinhui;Imanaka-Yoshida, Kyoko
Tenascin C (TNC) 是一种在实体瘤中上调的细胞外基质糖蛋白。乳腺癌的侵袭前沿显示较高的 TNC 表达，这与较差的患者预后相关。我们检查了 TNC 是否会诱导乳腺癌上皮间质转化 (EMT)。浸润性导管癌的免疫组织化学分析显示，间质中 TNC 沉积频繁，肿瘤周围边缘散有癌细胞。将 TNC 添加到 MCF-7 乳腺癌细胞的培养基中会引起 EMT 样变化以及 E-钙粘蛋白和 β-连环蛋白从细胞与细胞接触中的离域。尽管 EMT 后总裂解物中 E-钙粘蛋白和 β-连环蛋白的含量没有变化，但 Triton X-100 可溶性组分中的 E-钙粘蛋白和 β-连环蛋白含量有所增加，表明细胞从膜移动到胞质溶胶中。在伤口愈合测定中，细胞从伤口边缘分散，并且在 TNC 处理后显示出更快的迁移。 EMT 表型通过 SRC 底物位点 Y418 的磷酸化以及 Y861 和 Y925 的粘着斑激酶 (FAK) 的磷酸化与 SRC 激活相关。这些磷酸化蛋白与cry整合素阳性粘附斑共定位。 ay 的中和抗体或 SRC 激酶抑制剂可阻断 EMT。 TNC 可诱导乳腺癌细胞出现 EMT 样变化，显示细胞间粘附力丧失和迁移增强，这与 SRC 磷酸化 FAK 相关；这可能是观察到 TNC 在乳腺癌侵袭中的促进作用的原因。 (Am J Pathol 2011, 178:754-763; DOI: 10.1016/j.ajpath.2010.10.015)
Tenascin C (TNC) is an extracellular matrix glycoprotein up-regulated in solid tumors. Higher TNC expression is shown in invading fronts of breast cancer, which correlates with poorer patient outcome. We examined whether TNC induces epithelial-mesenchymal transition (EMT) in breast cancer. Immunohistochemical analysis of invasive ductal carcinomas showed that TNC deposition was frequent in stroma with scattered cancer cells in peripheral margins of tumors. The addition of TNC to the medium of the MCF-7 breast cancer cells caused EMT-like change and delocalization of E-cadherin and beta-catenin from cell-cell contact. Although amounts of E-cadherin and beta-catenin were not changed after EMT in total lysates, they were increased in the Triton X-100-soluble fractions, indicating movement from the membrane into the cytosoL In wound healing assay, cells were scattered from wound edges and showed faster migration after TNC treatment. The EMT phenotype was correlated with SRC activation through phosphorylation at Y418 and phosphorylation of focal adhesion kinase (FAK) at Y861 and Y925 of SRC substrate sites. These phosphorylated proteins colocalized with cry integrin-positive adhesion plaques. A neutralizing antibody against ay or a SRC kinase inhibitor blocked EMT. TNC could induce EMT-like change showing loss of intercellular adhesion and enhanced migration in breast cancer cells, associated with FAK phosphorylation by SRC; this may be responsible for the observed promotion of TNC in breast cancer invasion. (Am J Pathol 2011, 178:754-763; DOI: 10.1016/j.ajpath.2010.10.015)