Activating transcription factor 4 promotes esophageal squamous cell carcinoma invasion and metastasis in mice and is associated with poor prognosis in human patients.

Hongwu Zhu,Dayong Sun,Weibing Song,Bei Chen,Xiong Chen,Bin Chen,Yagang Zhao,Vladimir V Kalinichenko

doi:10.1371/journal.pone.0103882

Abstract

BackgroundActivating transcription factor 4 (ATF4) is a stress response gene that is involved in homeostasis and cellular protection. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remains unknown. In this study, we aimed to determine the clinicopathologic significance of ATF4 in ESCC and its potential role in ESCC invasion and metastasis.Methodology/Principal FindingsWe demonstrated that ATF4 overexpression is correlated with multiple malignant characteristics and indicates poor prognosis in ESCC patients. ATF4 expression was an independent factor that affected the overall survival of patients with ESCC after surgical resection. ATF4 promoted cell invasion and metastasis by promoting matrix metalloproteinase (MMP)-2 and MMP-7 expression, while its silencing significantly attenuated these activities both in vitro and in vivo.Conclusions/SignificanceWe report that ATF4 is a potential biomarker for ESCC prognosis and that its dysregulation may play a key role in the regulation of invasion and metastasis in ESCC cells. The targeting of ATF4 may provide a new strategy for blocking ESCC metastasis.

Highlights

Esophageal cancer is the sixth leading cause of cancer-related mortality with nearly 407,000 deaths occurring worldwide each year [1]
Conclusions/Significance: We report that Activating transcription factor 4 (ATF4) is a potential biomarker for esophageal squamous cell carcinoma (ESCC) prognosis and that its dysregulation may play a key role in the regulation of invasion and metastasis in ESCC cells
ATF4 expression correlates with advanced clinical stage, lymph node metastasis, and poor prognosis in ESCC patients

Summary

Introduction

Esophageal cancer is the sixth leading cause of cancer-related mortality with nearly 407,000 deaths occurring worldwide each year [1]. Several genes that are associated with ESCC metastasis have been identified, including Gadd45G [10], glioma-associated oncogene homolog 1 [11], lysine-specific demethylase 1 [12], maspin [13], PLCE1 [14], and CACNA2D3 [15]. These studies have indicated that specific genes may contribute to the metastasis of ESCC. We aimed to determine the clinicopathologic significance of ATF4 in ESCC and its potential role in ESCC invasion and metastasis

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Conclusion