Beijing International Science and Technology Cooperation Base of Antivirus Drug, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, P. R. China.
J Cell Physiol. 2019 Nov;234(11):20469-20484. doi: 10.1002/jcp.28648. Epub 2019 Apr 15.
Accumulating evidence suggests that Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is very crucial to regulate tumorigenesis and metastasis. Recently, many research works have suggested that G3BP1 is overexpressed in many human cancers including esophageal cancer. Nevertheless, the functional roles of G3BP1 in esophageal cancer are still unknown. Here, the results suggested that silencing of G3BP1 inhibited proliferation, migration, and invasion of esophageal cancer cells, whereas overexpression of G3BP1 led to opposite effects on the growth and metastasis. Surprisingly, G3BP1-depletion had no effect on cell death but caused the arrest of cell cycle in the G /G phase and increased the levels of p53 and p21. In addition, loss of G3BP1 led to a significant elevation of E-cadherin and decrease of N-cadherin, Vimentin, Snail, MMP-9, and MMP-2. Mechanistically, loss of G3BP1 dramatically suppressed Wnt-stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor activity and downregulated its target genes including c-Myc, Axin2, and cyclin D1. Moreover, knockdown of G3BP1 downregulated the expression levels of p-PI3K, p-AKT, and p-GSK-3β, but the total PI3K, AKT, and GSK-3β were not changed. Furthermore, our data proved that the promoting effects of G3BP1-overexpression on cell proliferation, migration, and invasion could be rescued by PI3K inhibitor LY294002 treatment. Collectively, our results here elucidate that G3BP1-depletion suppresses proliferation, migration, and invasion capabilities of esophageal cancer cells via the inactivation of Wnt/β-catenin and PI3K/AKT signaling pathways. Furthermore, our findings imply that G3BP1 can participate in the regulation of esophageal cancer progression, and will be taken as a promising target to treat esophageal cancer.
越来越多的证据表明，Ras GTPase 激活蛋白 SH3 结构域结合蛋白 1（G3BP1）对调节肿瘤发生和转移非常重要。最近，许多研究工作表明，G3BP1 在包括食管癌在内的许多人类癌症中过表达。然而，G3BP1 在食管癌中的功能作用尚不清楚。在这里，研究结果表明，沉默 G3BP1 抑制了食管癌细胞的增殖、迁移和侵袭，而过表达 G3BP1 则导致细胞生长和转移产生相反的效果。令人惊讶的是，G3BP1 耗竭对细胞死亡没有影响，但导致细胞周期停滞在 G1/G0 期，并增加了 p53 和 p21 的水平。此外，G3BP1 的缺失导致 E-钙黏蛋白水平显著升高，N-钙黏蛋白、波形蛋白、Snail、MMP-9 和 MMP-2 水平降低。在机制上，G3BP1 的缺失显著抑制了 Wnt 刺激的 T 细胞因子/淋巴增强因子（TCF/LEF）转录因子活性，并下调了其靶基因，包括 c-Myc、Axin2 和 cyclin D1。此外，G3BP1 的敲低降低了 p-PI3K、p-AKT 和 p-GSK-3β 的表达水平，但总 PI3K、AKT 和 GSK-3β 没有变化。此外，我们的数据证明，PI3K 抑制剂 LY294002 处理可以挽救 G3BP1 过表达对细胞增殖、迁移和侵袭的促进作用。总之，我们的研究结果表明，G3BP1 耗竭通过失活 Wnt/β-catenin 和 PI3K/AKT 信号通路抑制食管癌细胞的增殖、迁移和侵袭能力。此外，我们的研究结果表明，G3BP1 可以参与食管癌进展的调节，并且可以作为治疗食管癌的有前途的靶点。
