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Clin Cancer Res. 2014 Sep 1;20(17):4689-704. doi: 10.1158/1078-0432.CCR-14-0315. Epub 2014 Jul 1.

TMEFF2 deregulation contributes to gastric carcinogenesis and indicates poor survival outcome.

Author information

  • 1State 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.
  • 2Department of Pathology and Medicine, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island.
  • 3Department of Surgery, University of Michigan, Ann Arbor, Michigan.
  • 4State 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.
  • 5State 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.

Abstract

PURPOSE:

The role and clinical implication of the transmembrane protein with EGF and two follistatin motifs 2 (TMEFF2) in gastric cancer is poorly understood.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

TMEFF2 acts as a tumor suppressor in gastric cancer through direct interaction with SHP-1 and can be a potential biomarker of carcinogenesis.

©2014 American Association for Cancer Research.

PMID:
24987055
[PubMed - in process]
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