title: ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma.
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.
authors.affiliation: 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.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Yang-Min
authors.initials: YM
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.affiliation: 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.
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, P. R. China.
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: En-Min
authors.initials: EM
authors.lastname: Li
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D002945:Cisplatin