Department of Medicine, Knappschafts krankenhaus, Ruhr-University, In der Schornau 23-25, 44892 Bochum, Germany.
Anticancer Res. 2010 Jul;30(7):2603-13.
Inactivation of the tumour suppressor gene SMAD4 is a genetically late event in gastrointestinal carcinogenesis. SMAD4 is a transmitter of growth-inhibitory effects of transforming growth factor-beta (TGF-beta), an important tumour promoter capable of inducing an epithelial to mesenchymal transition (EMT). The role of SMAD proteins in late, tumour-promoting effects of TGF-beta is not well understood.
The change of molecular differentiation markers typical for EMT upon SMAD4 re-expression in SW480 cells was determined using Western blotting, immunohistochemistry and confocal laser microscopy. The influence of SMAD4 on the migration of SW480 cells was assessed in wound healing and pore migration assays.
SMAD4 suppresses invasiveness and mediates reversion of SW480 cells from a mesenchymal-like to a polarized epithelial phenotype, with features of enterocyte-like differentiation. Moreover, SMAD4 reconstitution was associated with down-regulation of endogenous TGF-beta cytokines, suggesting that autocrine TGF-beta signaling may be involved in the EMT.
These results provide further evidence for a role of SMAD4 as a regulator of invasion, a process of prime importance in carcinogenesis but hitherto poorly understood in molecular terms.
肿瘤抑制基因 SMAD4 的失活是胃肠道肿瘤发生过程中的一个遗传晚期事件。SMAD4 是转化生长因子-β（TGF-β）生长抑制作用的传递者，TGF-β是一种重要的肿瘤促进剂，能够诱导上皮间质转化（EMT）。SMAD 蛋白在 TGF-β晚期促进肿瘤的作用尚不清楚。
通过 Western blot、免疫组织化学和共聚焦激光显微镜检测 SW480 细胞中 SMAD4 再表达时 EMT 典型的分子分化标志物的变化。通过划痕愈合和孔迁移实验评估 SMAD4 对 SW480 细胞迁移的影响。
SMAD4 抑制侵袭，并介导 SW480 细胞从间充质样向极化上皮表型的逆转，具有肠细胞样分化的特征。此外，SMAD4 的重建与内源性 TGF-β细胞因子的下调相关，表明自分泌 TGF-β信号可能参与 EMT。
这些结果进一步证明 SMAD4 作为侵袭调节剂的作用，这是肿瘤发生过程中的一个重要过程，但目前在分子水平上尚不清楚。
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