Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12851-6. doi: 10.1073/pnas.1017372108. Epub 2011 Jul 18.
Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesenchymal cells. It plays an important role in development and tumor cell metastasis. However, the mechanisms of EMT and their dysfunction in cancer cells are still not well understood. Here we report that Siva1 interacts with stathmin, a microtubule destabilizer. Siva1 inhibits stathmin's activity directly as well as indirectly through Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells. In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1 in suppressing cell migration and EMT and indicate that down-regulation of Siva1 may contribute to tumor cell metastasis.
上皮-间充质转化 (EMT) 使上皮细胞获得运动性和侵袭性，这些特征是间充质细胞所具有的。它在上皮细胞的发育和肿瘤细胞转移中发挥着重要作用。然而，EMT 的机制及其在癌细胞中的功能障碍仍然不太清楚。在这里，我们报告 Siva1 与微管不稳定蛋白 stathmin 相互作用。Siva1 直接抑制 stathmin 的活性，也可以通过 Ca(2+)/钙调蛋白依赖性蛋白激酶 II 介导的 stathmin 的丝氨酸 16 位磷酸化间接抑制 stathmin 的活性。通过抑制 stathmin，Siva1 增强微管的形成并阻碍焦点黏附的组装、细胞迁移和 EMT。低水平的 Siva1 和 Ser16 磷酸化的 stathmin 与人类乳腺癌细胞的高转移状态相关。在小鼠模型中，Siva1 的敲低促进了癌症的扩散，而过表达 Siva1 则抑制了癌症的扩散。这些结果表明微管动力学对 EMT 至关重要。此外，它们揭示了 Siva1 在抑制细胞迁移和 EMT 中的重要作用，并表明 Siva1 的下调可能有助于肿瘤细胞的转移。
