Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA.
Cell Biosci. 2011 Dec 28;1:41. doi: 10.1186/2045-3701-1-41.
Smad proteins are classified in different groups based on their functions in mediating transforming growth factor β (TGFβ) superfamily components. Smad1/5/8 mainly mediate bone morphogenetic proteins (BMP) pathway and Smad2/3 mainly mediate TGFβ pathway. Smad4 functions as common Smad to mediate both pathways. Previous studies showed many members of TGFβ superfamily play a role in carcinogenesis. The current review focuses on the role of TGFβ signaling Smads in squamous cell carcinomas (SCCs). TGFβ signaling inhibits early tumor development, but promotes tumor progression in the late stage. Although Smad2, Smad3 and Smad4 are all TGFβ signaling Smads, they play different roles in SCCs. Genetically, Smad2 and Smad4 are frequently mutated or deleted in certain human cancers whereas Smad3 mutation or deletion is infrequent. Genetically engineered mouse models with these individual Smad deletions have provided important tools to identify their diversified roles in cancer. Using these models, we have shown that Smad4 functions as a potent tumor suppressor and its loss causes spontaneous SCCs development; Smad2 functions as a tumor suppressor and its loss promotes SCC formation initiated by other genetic insults but is insufficient to initiate tumor formation. In contrast, Smad3 primarily mediates TGFβ-induced inflammation. The functions of each Smad also depends on the presence/absence of its Smad partner, thus need to be interpreted in a context-specific manner.
Smad 蛋白根据其在转化生长因子 β（TGFβ）超家族成分中的作用分为不同的组。Smad1/5/8 主要介导骨形态发生蛋白（BMP）途径，Smad2/3 主要介导 TGFβ 途径。Smad4 作为共同 Smad 发挥作用，介导两条途径。先前的研究表明，TGFβ 超家族的许多成员在致癌作用中发挥作用。本综述重点介绍 TGFβ 信号 Smads 在鳞状细胞癌（SCCs）中的作用。TGFβ 信号在早期肿瘤发展中起抑制作用，但在晚期促进肿瘤进展。尽管 Smad2、Smad3 和 Smad4 都是 TGFβ 信号 Smads，但它们在 SCCs 中发挥不同的作用。在遗传上，Smad2 和 Smad4 在某些人类癌症中经常发生突变或缺失，而 Smad3 突变或缺失则不常见。具有这些单个 Smad 缺失的基因工程小鼠模型为确定它们在癌症中的多样化作用提供了重要工具。使用这些模型，我们表明 Smad4 作为一种有效的肿瘤抑制因子发挥作用，其缺失导致自发性 SCCs 发展；Smad2 作为肿瘤抑制因子发挥作用，其缺失促进其他遗传损伤引发的 SCC 形成，但不足以引发肿瘤形成。相比之下，Smad3 主要介导 TGFβ 诱导的炎症。每个 Smad 的功能还取决于其 Smad 伴侣的存在/缺失，因此需要以特定于上下文的方式进行解释。
