Shp2 Plays a Critical Role in IL-6-Induced EMT in Breast Cancer Cells.
Shp2 Plays a Critical Role in IL-6-Induced EMT in Breast Cancer Cells.
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Shp2 在 IL-6 诱导的乳腺癌细胞 EMT 中发挥关键作用
DOI：
10.3390/ijms18020395
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发表时间：
2017-02-13
影响因子：
5.6
通讯作者：
Niu R
中科院分区：
文献类型：
--
作者：
Sun X;Zhang J;Wang Z;Ji W;Tian R;Zhang F;Niu R
越来越多的证据表明，蛋白质酪氨酸磷酸酶 Shp2 在多种癌症中发挥着强大的肿瘤促进作用。 Shp2 的异常表达与许多人类恶性肿瘤有关。癌症组织中Shp2的过度表达与癌症转移、靶向治疗耐药和不良预后相关。 Shp2 众所周知的功能是其在调节由生长因子和细胞因子（包括白细胞介素 6 (IL-6)）引发的细胞信号传导方面的积极作用。最近的几项研究表明，Shp2 是生长因子触发的上皮间质转化 (EMT) 所必需的。然而，Shp2 是否参与 IL-6 信号传导促进的乳腺癌 EMT 和进展仍不清楚。在这项研究中，我们发现外源性和内源性IL-6可以通过促进EMT来增强乳腺癌的侵袭和迁移。 IL-6 还诱导 Erk1/2 的激活和 Shp2 的磷酸化。 Shp2 的敲除减弱了 IL-6 诱导的 E-钙粘蛋白下调，以及 IL-6 促进的细胞迁移和侵袭。此外，通过使用Shp2磷酸酶突变体、磷酸酪氨酸模拟突变体和缺陷突变体，我们提供了证据，证明Shp2的磷酸酶活性及其酪氨酸磷酸化对于IL-6诱导的E-钙粘蛋白下调和Erk1/2磷酸化是必需的。我们的研究结果揭示了将 Shp2 与 IL-6 促进的乳腺癌进展联系起来的重要功能。
Accumulative evidence demonstrates that the protein tyrosine phosphatase Shp2 functions as a powerful tumor promoter in many types of cancers. Abnormal expression of Shp2 has been implicated in many human malignancies. Overexpression of Shp2 in cancer tissues is correlated with cancer metastasis, resistance to targeted therapy, and poor prognosis. The well-known function of Shp2 is its positive role in regulating cellular signaling initiated by growth factors and cytokines, including interleukin-6 (IL-6). Several recent studies have shown that Shp2 is required for epithelial-mesenchymal transition (EMT), triggered by growth factors. However, whether Shp2 is involved in IL-6-signaling-promoted breast cancer EMT and progression, remains undefined. In this study, we showed that exogenous and endogenous IL-6 can enhance breast cancer invasion and migration, through the promotion of EMT. IL-6 also induces the activation of Erk1/2 and the phosphorylation of Shp2. Knockdown of Shp2 attenuated the IL-6-induced downregulation of E-cadherin, as well as IL-6-promoted cell migration and invasion. Moreover, by using Shp2 phosphatase mutants, phosphor-tyrosine mimicking, and deficiency mutants, we provided evidence that the phosphatase activity of Shp2 and its tyrosine phosphorylation, are necessary for the IL-6-induced downregulation of E-cadherin and the phosphorylation of Erk1/2. Our findings uncover an important function that links Shp2 to IL-6-promoted breast cancer progression.