FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway.

Yeo Yeo,Ito Ito,Jammula Jammula,Suda Suda,Wong Wong,Goh Goh,Yong Yong,Balcıoğlu Balcıoğlu,Xie Xie,Ladoux Ladoux,Peethala Peethala,Zhou Zhou,Subhash Subhash,Thuya Thuya,Wang Wang,Loh Loh,Yang Yang,Tan Tan

doi:10.3390/cancers11060836

Abstract

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.

Highlights

Gastric cancer is the fifth most commonly diagnosed malignancy and the third leading cause of cancer-related death worldwide [1]
We investigated the role of F-box/WD repeat-containing protein 5 (FBXW5) in the regulation of tumorigenesis and metastasis, as well as its effect on the focal adhesion kinase (FAK)-Src pathway
FBXW5 expression was knocked down in MKN1 cells using FBXW5 targeted siRNAs to investigate the role of FBXW5 in gastric cancer cell proliferation (Figure 1A,B)

Summary

Introduction

Gastric cancer is the fifth most commonly diagnosed malignancy and the third leading cause of cancer-related death worldwide [1]. The worldwide incidence of gastric cancer has declined remarkably over the recent few decades [2,3,4], disease burden remains high and gastric cancer is traditionally associated with poor prognosis. Poor gastric cancer prognosis is attributed to the late diagnosis in most patients. This is because most patients are asymptomatic in the early stage [5], with most cases often diagnosed in the late stages when metastatic gastric cancer has developed. Statistics have shown that 79% of patients are diagnosed at stage IV, with a less than 5% five-year survival rate. Gastric cancer metastasis is a serious condition whereby the median overall survival does not exceed one year [6]

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Discussion

Conclusion