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They also drive intestinal stem cell proliferation and positioning, control intestinal tissue boundaries and are involved in liver, pancreatic and colorectal cancers, indicating involvement in additional digestive system malignancies. We investigated the role of Ephrin\u2010B4 receptor (EPHB4), and its ligand EFNB2, in gastric and gastroesophageal junction cancers in patient cohorts through computational, mathematical, molecular and immunohistochemical analyses. We show that EPHB4 is upregulated in preneoplastic gastroesophageal lesions and its expression further increased in gastroesophageal cancers in several independent cohorts. The closely related EPHB6 receptor, which also binds EFNB2, was downregulated in all tested cohorts, consistent with its tumor\u2010suppressive properties in other cancers. EFNB2 expression is induced in esophageal cells by acidity, suggesting that gastroesophageal reflux disease (GERD) may constitute an early triggering event in activating EFNB2\u2013EPHB4 signaling. Association of EPHB4 to both Barrett's esophagus and to advanced tumor stages, and its overexpression at the tumor invasion front and vascular endothelial cells intimate the notion that EPHB4 may be associated with multiple steps of gastroesophageal tumorigenesis. Analysis of oncogenomic signatures uncovered the first EPHB4\u2010associated gene network (false discovery rate: 7 \u00d7 10<jats:sup>\u221290<\/jats:sup>) composed of a five\u2010transcription factor interconnected gene network that drives proliferation, angiogenesis and invasiveness. The EPHB4 oncogenomic network provides a molecular basis for its role in tumor progression and points to EPHB4 as a potential tumor aggressiveness biomarker and drug target in gastroesophageal cancers.<\/jats:p>","DOI":"10.1002\/ijc.29865","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T19:44:56Z","timestamp":1443469496000},"page":"1220-1231","source":"Crossref","is-referenced-by-count":16,"title":["Differential protein expression and oncogenic gene network link tyrosine kinase ephrin B4 receptor to aggressive gastric and gastroesophageal junction cancers"],"prefix":"10.1002","volume":"138","author":[{"given":"Britta","family":"Liersch\u2010L\u00f6hn","sequence":"first","affiliation":[{"name":"Department of Surgery Sana Klinikum Lichtenberg Berlin Berlin Germany"},{"name":"Department of General Vascular and Thoracic Surgery, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin Berlin 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