FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway
FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway
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DOI：
10.3390/cancers11060836
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发表时间：
2019-06-01
期刊：
影响因子：
5.2
通讯作者：
Yong, Wei Peng
中科院分区：
文献类型：
--
作者：
Yeo, Mei Shi;Subhash, Vinod Vijay;Yong, Wei Peng
含有 F-box/WD 重复序列的蛋白 5 (FBXW5) 是 F-box 蛋白 FBXW 亚类的成员。尽管FBXW5作为Skpl-Cullin-F-box (SCF)泛素连接酶复合物的一个组成部分的功能已知，但FBXW5在胃癌肿瘤发生和转移中的作用尚未得到研究。本研究探讨FBXW5在肿瘤发生和转移中的作用，以及对胃癌关键信号通路的调控；使用体外 FBXW5 敲低/过表达细胞系和体内模型。 FBXW5 的体外敲低会导致细胞增殖和细胞周期进程减少，同时细胞凋亡和 caspase-3 活性增加。此外，FBXW5 的敲低还会导致细胞迁移和粘附的下调，其特征是肌动蛋白聚合、粘着斑周转和牵引力的减少。这项研究还描述了 FBXW5 在致癌信号传导中的机制作用，因为它的抑制作用下调了 RhoA-ROCK 1（Rho 相关蛋白激酶 1）和粘着斑激酶 (FAK) 信号级联。 FBXW5 的过表达促进体内肿瘤生长，而其抑制则下调体内肿瘤转移。综合考虑，我们的研究确定了 FBXW5 在胃癌中的新致癌作用，并引起了人们对其作为潜在治疗靶点的临床实用性的进一步兴趣。
F-box/WD repeat-containing protein 5 (FBXW5) is a member of the FBXW subclass of F-box proteins. Despite its known function as a component of the Skpl-Cullin-F-box (SCF) ubiquitin ligase complex, the role of FBXW5 in gastric cancer tumorigenesis and metastasis has not been investigated. The present study investigates the role of FBXW5 in tumorigenesis and metastasis, as well as the regulation of key signaling pathways in gastric cancer; using in-vitro FBXW5 knockdown/overexpression cell line and in-vivo models. In-vitro knockdown of FBXW5 results in a decrease in cell proliferation and cell cycle progression, with a concomitant increase in cell apoptosis and caspase-3 activity. Furthermore, knockdown of FBXW5 also leads to a down regulation in cell migration and adhesion, characterized by a reduction in actin polymerization, focal adhesion turnover and traction forces. This study also delineates the mechanistic role of FBXW5 in oncogenic signaling as its inhibition down regulates RhoA-ROCK 1 (Rho-associated protein kinase 1) and focal adhesion kinase (FAK) signaling cascades. Overexpression of FBXW5 promotes in-vivo tumor growth, whereas its inhibition down regulates in-vivo tumor metastasis. When considered together, our study identifies the novel oncogenic role of FBXW5 in gastric cancer and draws further interest regarding its clinical utility as a potential therapeutic target.