Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition
Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition
复制标题
Shp2通过减弱PAR3/PAR6/aPKC极性蛋白复合物和增强上皮间质转化来促进前列腺癌的转移
DOI：
10.1038/onc.2015.184
复制
发表时间：
2016-03-10
期刊：
影响因子：
8
通讯作者：
Gao, W-Q
中科院分区：
文献类型：
--
作者：
Zhang, K.;Zhao, H.;Gao, W-Q
上皮间质转化（EMT），以细胞间连接的溶解、细胞极性的丧失和细胞运动性的增加为标志，是前列腺癌转移的重要步骤之一。然而，其根本机制尚未得到充分探索。我们在这项研究中报告说，Shp2 在前列腺癌中表达上调，并且与不良的疾病结果相关，即肿瘤转移和患者生存期缩短。野生型Shp2或致癌Shp2突变体的过度表达会导致前列腺癌细胞增殖、集落和球体形成以及体内肿瘤形成增加。在 Shp2 敲低细胞中观察到相反的效果。此外，Shp2促进前列腺肿瘤细胞的体外迁移和体内转移。从机制上讲，Shp2 通过其 Src 同源-2 结构域与 PAR3（分区缺陷 3）相互作用。 Shp2 的异位表达会减弱 PAR3 的磷酸化和 PAR3/PAR6/非典型蛋白激酶 C 极性蛋白复合物的形成，导致细胞极性破坏、细胞间连接失调和 EMT 增加。这些发现提供了一种新的机制，致癌信号转导分子可通过该机制调节细胞极性和诱导 EMT。
Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell-cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell-cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT.