Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
复制标题
DOI：
10.1111/j.1755-148x.2010.00758.x
复制
发表时间：
2010-12
影响因子：
4.3
通讯作者：
Rosenthal DS
中科院分区：
文献类型：
--
作者：
DiVito KA;Trabosh VA;Chen YS;Chen Y;Albanese C;Javelaud D;Mauviel A;Simbulan-Rosenthal CM;Rosenthal DS
非经典TGF-β信号传导中的TGF-β相关蛋白的列表正在增长。实例包括指导微小RNA加工的受体-Smads和指导细胞粘附的细胞-Smads，例如Smad 7。带有荧光标记的黑色素瘤细胞的人类皮肤移植物显示，Smad 7表达细胞将自身定位在真皮-表皮交界处附近，并且未能形成肿瘤，而对照细胞容易侵入并在真皮内形成肿瘤。Smad 7显著抑制与降解相关的β-catenin T41/S45磷酸化，并诱导全长N-钙粘蛋白增加4.5倍。细胞粘附试验证实了Smad 7表达细胞和通过N-钙粘蛋白介导的原代真皮成纤维细胞之间的强相互作用，而对照细胞不能进行这种相互作用。皮肤移植物的免疫荧光分析表明，与对照黑色素瘤细胞相比，Smad 7细胞和原代真皮成纤维细胞表面的N-钙粘蛋白同型相互作用。我们认为Smad 7抑制β-catenin降解并促进与N-cadherin的相互作用，稳定与邻近真皮成纤维细胞的结合，从而减轻侵袭。
The list of TGF-β-related proteins in non-canonical TGF-β signaling is growing. Examples include receptor-Smads directing micro-RNA processing and inhibitory-Smads, e.g. Smad7, directing cell adhesion. Human skin grafts with fluorescently-tagged melanoma cells revealed Smad7-expressing cells positioned themselves proximal to the dermal-epidermal junction and failed to form tumors, while control cells readily invaded and formed tumors within the dermis. Smad7 significantly inhibited β-catenin T41/S45 phosphorylation associated with degradation and induced a 4.5-fold increase in full-length N-cadherin. Cell adhesion assays confirmed a strong interaction between Smad7-expressing cells and primary dermal fibroblasts mediated via N-cadherin; while control cells were incapable of such interaction. Immunofluorescent analysis of skin grafts indicated N-cadherin homotypic interaction at the surface of both Smad7 cells and primary dermal fibroblasts, in contrast to control melanoma cells. We propose that Smad7 suppresses β-catenin degradation and promotes interaction with N-cadherin, stabilizing association with neighboring dermal fibroblasts, thus mitigating invasion.