ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma

Jian-Jun Xie; Yang-Min Xie; Bo Chen; Feng Pan; Jin-Cheng Guo; Qing Zhao; Jin-Hui Shen; Zhi-Yong Wu; Jian-Yi Wu; Li-Yan Xu; En-Min Li

doi:10.18632/oncotarget.2322

ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma

Oncotarget. 2014 Sep 30;5(18):8569-82. doi: 10.18632/oncotarget.2322.

Authors

Jian-Jun Xie¹, Yang-Min Xie², Bo Chen³, Feng Pan¹, Jin-Cheng Guo¹, Qing Zhao³, Jin-Hui Shen⁴, Zhi-Yong Wu⁵, Jian-Yi Wu¹, Li-Yan Xu³, En-Min Li¹

Affiliations

¹ Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, P. R. China. Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 515041, P. R. China.
² Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, P. R. China. Department of Experimental Animal Center, Medical College of Shantou University, Shantou 515041, P. R. China.
³ Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, P. R. China. Institute of Oncologic Pathology, Medical College of Shantou University, Shantou 515041, P. R. China.
⁴ Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, P. R. China.
⁵ Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, P. R. China. Department of Oncologic Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, P. R. China.

Abstract

ATF3 was a transcription factor involved in the progression of certain cancers. Here, we sought to explore the expression and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). The prognostic significance of ATF3 expression was evaluated in 150 ESCC samples and 21 normal squamous cell epithelium tissues. Results showed that ATF3 was down-regulated in ESCC lesions compared with paired non-cancerous tissues and low tumorous ATF3 expression significantly correlated with shorter overall survival (OS) and disease-free survival (DFS). Cox regression analysis confirmed that ATF3 expression was an independent prognostic factor. Experimentally, forced expression of ATF3 led to decreased growth and invasion properties of ESCC cells in vitro and in vivo, whereas knockdown of ATF3 did the opposite. Furthermore, ATF3 upregulated the expression of MDM2 by increasing the nuclear translocation of P53 and formed an ATF3/MDM2/MMP-2 complex that facilitated MMP-2 degradation, which subsequently led to inhibition of cell invasion. Finally, we showed that Cisplatin could restrain the invasion of ESCC cells by inducing the expression of ATF3 via P53 signaling. Combined, our findings highlight a suppressed role for ATF3 in ESCC and targeting ATF3 might be a potential therapeutic strategy.

Publication types

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

MeSH terms

Activating Transcription Factor 3 / genetics
Activating Transcription Factor 3 / metabolism*
Animals
Antineoplastic Agents / pharmacology
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / secondary
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cisplatin / pharmacology
Disease-Free Survival
Dose-Response Relationship, Drug
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / mortality
Esophageal Neoplasms / pathology
Esophageal Squamous Cell Carcinoma
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Male
Matrix Metalloproteinase 2 / metabolism
Mice, Nude
Neoplasm Invasiveness
Proportional Hazards Models
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA Interference
Signal Transduction
Time Factors
Transfection
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Xenograft Model Antitumor Assays

Substances

ATF3 protein, human
Activating Transcription Factor 3
Antineoplastic Agents
Biomarkers, Tumor
TP53 protein, human
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
MMP2 protein, human
Matrix Metalloproteinase 2
Cisplatin