title: Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma.
abstract: The mechanism underlying the progression of normal esophageal mucosa to esophageal adenocarcinoma remains elusive. WNT5A is a noncanonical WNT, which mainly functions via the receptor tyrosine kinase-like orphan receptor 2 (ROR2), and has an unclear role in carcinogenesis. In this study, we aimed to determine the role of WNT5A/ROR2 signaling in esophageal adenocarcinoma. Analysis of WNT5A and ROR2 expression patterns in healthy controls, Barrett and esophageal adenocarcinoma patients' esophageal clinical specimens as well as in various esophageal cell lines demonstrated a ROR2 overexpression in esophageal adenocarcinoma tissues compared with Barrett and healthy mucosa, whereas WNT5A expression was found significantly downregulated toward esophageal adenocarcinoma formation. Treatment of esophageal adenocarcinoma OE33 cells with human recombinant WNT5A (rhWNT5A) significantly suppressed proliferation, survival, and migration in a dose-dependent fashion. rhWNT5A was found to inhibit TOPflash activity in ROR2 wild-type cells, whereas increased TOPflash activity in ROR2-knockdown OE33 cells. In addition, ROR2 knockdown alone abolished cell proliferation and weakened the migration properties of OE33 cells. These findings support an early dysregulation of the noncanonical WNT5A/ROR2 pathway in the pathogenesis of esophageal adenocarcinoma, with the loss of WNT5A expression together with the ROR2 overexpression to be consistent with tumor promotion.
  
  
  
  The dysregulation of WNT5A/ROR2 noncanonical WNT signaling in Barrett-associated esophageal adenocarcinoma introduces possible prognostic markers and novel targets for tailored therapy of this malignancy. Mol Cancer Res; 14(7); 647-59. ©2016 AACR.
authors.affiliation: Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital, Leipzig, Germany.
authors.forename: Orestis
authors.initials: O
authors.lastname: Lyros
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Linghui
authors.initials: L
authors.lastname: Nie
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Tami
authors.initials: T
authors.lastname: Moore
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Medda
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Mary
authors.initials: M
authors.lastname: Otterson
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Behnaz
authors.initials: B
authors.lastname: Behmaram
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mackinnon
authors.affiliation: Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital, Leipzig, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Gockel
authors.affiliation: Division of Gastroenterology & Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Reza
authors.initials: R
authors.lastname: Shaker
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. prafiee@mcw.edu.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Rafiee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D000071818:Wnt-5a Protein / Q000378:metabolism*; D055815:Young Adult
chemical_list: C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors