Low FAT4 expression is associated with a poor prognosis in gastric cancer patients.

Xiaoting Jiang,Jungang Luo,Houquan Tao,Ji Xu,Yingjie Xia,Zhengchuang Liu,Xujun He

doi:10.18632/oncotarget.23702

Abstract

In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC. Methylation-specific PCR analysis showed increased FAT4 promoter methylation in GC tumor tissues and cell lines. Higher FAT4 promoter methylation was associated with low FAT4 expression and a poor prognosis. BGC-823 cells showed increased FAT4 expression upon treatment with 5-azacytidine, demethylating agent. FAT4 knockdown in BGC-823 cells led to increased cell proliferation, migration and invasiveness. Moreover, xenografts of BGC-823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients.

Highlights

Despite recent developments in the surgical techniques and improved efficacy of anticancer drugs, mortality rates of gastric cancer (GC) patients remains very high
We investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression
Xenografts of BGC823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients

Summary

Introduction

Despite recent developments in the surgical techniques and improved efficacy of anticancer drugs, mortality rates of gastric cancer (GC) patients remains very high. The Fat gene family was originally identified in Drosophila as a member of the cadherin super-family with tumor suppressor functions [2, 3]. It regulates cell proliferation and planar cell polarity during Drosophila development by the Hippo signaling pathway [4, 5]. They encode a type 1 trans-membrane protein with 34 cadherin repeats, 4 epidermal growth factor (EGF)-like repeats, a transmembrane domain and a cytoplasmic domain that is distinct from the classical cadherin proteins [6, 7]. FAT4 mediates key developmental functions such as planar cell polarity and regulates the Hippo signaling pathway, which controls the size of the organs [3, 4]

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