Ungefroren Hendrik, Witte David, Lehnert Hendrik
First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, and University of Lübeck, Lübeck, Germany.
Department of General and Thoracic Surgery, UKSH, Campus Kiel, Kiel, Germany.
Dev Dyn. 2018 Mar;247(3):451-461. doi: 10.1002/dvdy.24505. Epub 2017 May 30.
This article focuses on the role of Rho family GTPases, particularly Rac1 and Rac1b in TGF-β-induced epithelial-mesenchymal transition (EMT) and EMT-associated responses such as cell migration, invasion, and metastasis in cancer. EMT is considered a prerequisite for cells to adopt a motile and invasive phenotype and eventually become metastatic. A major regulator of EMT and metastasis in cancer is TGF-β, and its specific functions on tumor cells are mediated beside Smad proteins and mitogen-activated protein kinases (MAPKs) by small GTPases of the Rho/Rac1 family. Available data point to extensive signaling crosstalk between TGF-β and various Rho GTPases, and in particular a synergistic role of Rho and Rac1 during EMT and cell motility in normal and neoplastic epithelial cells. In contrast, the Rac1-related isoform, Rac1b, emerges as an endogenous inhibitor of Rac1 in TGF-β signaling, at least in pancreatic carcinoma cells. Given the tumor-promoting role of TGF-β in late-stage carcinomas and the intimate crosstalk of Rho/Rac1/Rac1b and TGF-β signaling in various tumor cell responses, targeting specific Rho GTPases may allow for selective interference with prooncogenic TGF-β responses to aid in anticancer treatments. Developmental Dynamics 247:451-461, 2018. © 2017 Wiley Periodicals, Inc.
本文聚焦于Rho家族GTP酶的作用，尤其是Rac1和Rac1b在转化生长因子-β（TGF-β）诱导的上皮-间质转化（EMT）以及EMT相关反应（如癌症中的细胞迁移、侵袭和转移）中的作用。EMT被认为是细胞获得运动性和侵袭性表型并最终发生转移的先决条件。癌症中EMT和转移的一个主要调节因子是TGF-β，其在肿瘤细胞上的特定功能除了通过Smad蛋白和丝裂原活化蛋白激酶（MAPK）介导外，还由Rho/Rac1家族的小GTP酶介导。现有数据表明TGF-β与各种Rho GTP酶之间存在广泛的信号串扰，尤其是在正常和肿瘤上皮细胞的EMT和细胞运动过程中，Rho和Rac1具有协同作用。相比之下，Rac1相关异构体Rac1b在TGF-β信号传导中作为Rac1的内源性抑制剂出现，至少在胰腺癌细胞中如此。鉴于TGF-β在晚期癌症中的促肿瘤作用以及Rho/Rac1/Rac1b与TGF-β信号在各种肿瘤细胞反应中的密切串扰，靶向特定的Rho GTP酶可能有助于选择性干扰促癌性TGF-β反应，从而辅助抗癌治疗。《发育动力学》247:451 - 461，2018年。©2017威利期刊公司。
