title: TMEFF2 deregulation contributes to gastric carcinogenesis and indicates poor survival outcome.
abstract: OBJECTIVE
  The role and clinical implication of the transmembrane protein with EGF and two follistatin motifs 2 (TMEFF2) in gastric cancer is poorly understood.
  
  
  METHODS
  Gene expression profile analyses were performed and Gene Set Enrichment Analysis (GSEA) was used to explore its gene signatures. AGS and MKN45 cells were transfected with TMEFF2 or control plasmids and analyzed for gene expression patterns, proliferation, and apoptosis. TMEFF2 expression was knocked down with shRNAs, and the effects on genome stability were assessed. Interactions between TMEFF2 and SHP-1 were determined by mass spectrometry and immunoprecipitation assays.
  
  
  RESULTS
  Integrated analysis revealed that TMEFF2 expression was significantly decreased in gastric cancer cases and its expression was negatively correlated with the poor pathologic stage, large tumor size, and poor prognosis. GSEA in The Cancer Genome Atlas (TCGA) and Jilin datasets revealed that cell proliferation, apoptosis, and DNA damage-related genes were enriched in TMEFF2 lower expression patients. Gain of TMEFF2 function decreased cell proliferation by increasing of apoptosis and blocking of cell cycle in gastric cancer cells. The protein tyrosine phosphatase SHP-1 was identified as a binding partner of TMEEF2 and mediator of TMEFF2 function. TMEFF2 expression positively correlated with SHP-1, and a favorable prognosis was more likely in patients with gastric cancer with higher levels of both TMEFF2 and SHP-1.
  
  
  CONCLUSIONS
  TMEFF2 acts as a tumor suppressor in gastric cancer through direct interaction with SHP-1 and can be a potential biomarker of carcinogenesis.
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Sun
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Du
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xiong
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Weng
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Ren
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yingxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Pathology and Medicine, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Weibiao
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China. jiehong97@gmail.com chenhaoyan@gmail.com jingyuanfang@yahoo.com.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China. Department of Pathology and Medicine, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island. jiehong97@gmail.com chenhaoyan@gmail.com jingyuanfang@yahoo.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China. jiehong97@gmail.com chenhaoyan@gmail.com jingyuanfang@yahoo.com.
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C423567:TMEFF2 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6