Yeo Mei Shi, Subhash Vinod Vijay, Suda Kazuto, Balcıoğlu Hayri Emrah, Zhou Siqin, Thuya Win Lwin, Loh Xin Yi, Jammula Sriganesh, Peethala Praveen C, Tan Shi Hui, Xie Chen, Wong Foong Ying, Ladoux Benoit, Ito Yoshiaki, Yang Henry, Goh Boon Cher, Wang Lingzhi, Yong Wei Peng
Department of Haematology-Oncology, National University Hospital of Singapore, Singapore 119228, Singapore.
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Cancers (Basel). 2019 Jun 17;11(6):836. doi: 10.3390/cancers11060836.
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 Skp1-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.
含F-box/ WD重复序列蛋白5（FBXW5）是F-box蛋白的FBXW亚类成员。尽管已知其作为Skp1-Cullin-F-box（SCF）泛素连接酶复合体的一个组成部分发挥作用，但FBXW5在胃癌发生和转移中的作用尚未得到研究。本研究利用体外FBXW5敲低/过表达细胞系和体内模型，研究FBXW5在胃癌发生、转移以及关键信号通路调控中的作用。体外敲低FBXW5会导致细胞增殖和细胞周期进程减少，同时细胞凋亡和半胱天冬酶-3活性增加。此外，敲低FBXW5还会导致细胞迁移和黏附下调，其特征是肌动蛋白聚合、黏着斑周转和牵引力降低。本研究还阐述了FBXW5在致癌信号传导中的机制作用，因为其抑制作用会下调RhoA-ROCK 1（Rho相关蛋白激酶1）和黏着斑激酶（FAK）信号级联。FBXW5的过表达促进体内肿瘤生长，而其抑制作用则下调体内肿瘤转移。综合来看，我们的研究确定了FBXW5在胃癌中的新致癌作用，并进一步引发了对其作为潜在治疗靶点的临床应用的关注。
