p120-catenin is required for the collective invasion of squamous cell carcinoma cells via a phosphorylation-independent mechanism
p120-catenin is required for the collective invasion of squamous cell carcinoma cells via a phosphorylation-independent mechanism
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DOI：
10.1038/sj.onc.1210334
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发表时间：
2007-08-09
期刊：
影响因子：
8
通讯作者：
Brunton, V. G.
中科院分区：
文献类型：
--
作者：
Macpherson, I. R.;Hooper, S.;Brunton, V. G.
E-钙粘附素介导的细胞-细胞连接缺失与癌细胞侵袭和患者生存不良有关。P120-catenin在促进E-cadherin的稳定性和黏附连接完整性方面发挥了关键作用，并被认为是一种潜在的侵袭抑制因子，它可以阻止细胞从钙粘附素介导的细胞-细胞黏附的限制中释放出来。然而，有人提出，p120的酪氨酸磷酸化可能在侵袭过程中参与钙粘素依赖的连接解体。在这里，我们在A431细胞中使用小干扰RNA(SiRNA)来表明p120的敲除促进了细胞的二维迁移。相反，p120基因敲除可减弱表皮生长因子诱导的A431在三维基质凝胶或器官培养中的侵袭，而siRNA抗性p120或不能在酪氨酸上磷酸化的p120亚型的重新表达，可恢复A431细胞在体外的集体侵袭模式。因此，p120以不依赖于磷酸化的方式促进A431细胞的侵袭。我们发现，A431细胞的集体侵袭依赖于钙粘蛋白介导的(P-和E-钙粘蛋白)细胞-细胞接触的存在，在p120表达被下调的细胞中，这种接触是丢失的。此外，p120在肿瘤中的浸润性鳞状细胞癌中表达，提示p120在体内肿瘤细胞的集体侵袭中可能是重要的。
Loss of E-cadherin-mediated cell-cell junctions has been correlated with cancer cell invasion and poor patient survival. p120-catenin has emerged as a key player in promoting E-cadherin stability and adherens junction integrity and has been proposed as a potential invasion suppressor by preventing release of cells from the constraints imposed by cadherin-mediated cell-cell adhesion. However, it has been proposed that tyrosine phosphorylation of p120 may contribute to cadherin-dependent junction disassembly during invasion. Here, we use small interfering RNA ( siRNA) in A431 cells to show that knockdown of p120 promotes two-dimensional migration of cells. In contrast, p120 knockdown impairs epidermal growth factor-induced A431 invasion into three-dimensional matrix gels or in organotypic culture, whereas re-expression of siRNA-resistant p120, or a p120 isoform that cannot be phosphorylated on tyrosine, restores the collective mode of invasion employed by A431 cells in vitro. Thus, p120 promotes A431 cell invasion in a phosphorylation-independent manner. We show that the collective invasion of A431 cells depends on the presence of cadherin-mediated (P- and E-cadherin) cell-cell contacts, which are lost in cells where p120 expression is knocked down. Furthermore, membranous p120 is maintained in invasive squamous cell carcinomas in tumours suggesting that p120 may be important for the collective invasion of tumours cells in vivo.