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; Xiong Chen; Bin Chen; Bei Chen; Weibing Song; Dayong Sun; Yagang Zhao

doi:10.1371/journal.pone.0103882

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

PLoS One. 2014 Jul 31;9(7):e103882. doi: 10.1371/journal.pone.0103882. eCollection 2014.

Authors

Hongwu Zhu¹, Xiong Chen², Bin Chen³, Bei Chen³, Weibing Song⁴, Dayong Sun¹, Yagang Zhao¹

Affiliations

¹ Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
² Department of Oncology, Fuzhou General Hospital of the Nanjing Military Command of the PLA, Fuzhou, China.
³ Department of Oncology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
⁴ Department of Gerontology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.

Abstract

Background: Activating 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 findings: We 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/significance: We 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4 / physiology*
Aged
Animals
Biomarkers, Tumor / metabolism
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / secondary
Cell Line, Tumor
Cell Movement
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / mortality
Esophageal Neoplasms / pathology
Female
Humans
Kaplan-Meier Estimate
Liver Neoplasms / metabolism*
Liver Neoplasms / mortality
Liver Neoplasms / secondary
Lung Neoplasms / metabolism*
Lung Neoplasms / mortality
Lung Neoplasms / secondary
Male
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 7 / metabolism
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Multivariate Analysis
Neoplasm Invasiveness
Neoplasm Transplantation
Prognosis
Proportional Hazards Models

Substances

ATF4 protein, human
Biomarkers, Tumor
Activating Transcription Factor 4
MMP7 protein, human
Matrix Metalloproteinase 7
MMP2 protein, human
Matrix Metalloproteinase 2

Grants and funding

This study was supported by combined grants from the National Natural Science Foundation of China (No. 81101821, No. 81101822), the Natural Science Foundation of Guangdong province (No. 10451001002004732), the Ph.D. Start-up Fund of Natural Science Foundation of Guangdong Province (No. S2011040001277), the Science and Technology Plan Project of Guangdong province (No. 2011B031800317), the Science and Technology Plan Project of Fujian province (No. 2012J05157), and the Science and Technology Key Project of Guangzhou (No. 11C26090521), China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.