Faculty Collaboration Database

Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma. Mol Cancer Res 2016 Jul;14(7):647-59

Date

04/17/2016

Pubmed ID

27084312

DOI

10.1158/1541-7786.MCR-15-0484

Scopus ID

2-s2.0-84979942182 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

UNLABELLED: 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.

IMPLICATIONS: 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.

Author List

Lyros O, Nie L, Moore T, Medda R, Otterson M, Behmaram B, Mackinnon A, Gockel I, Shaker R, Rafiee P

Authors

Mary F. Otterson MD Professor in the Surgery department at Medical College of Wisconsin
Reza Shaker MD Assoc Provost, Sr Assoc Dean, Ctr Dir, Chief, Prof in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Adult
Aged
Barrett Esophagus
Cell Proliferation
Disease Progression
Esophageal Neoplasms
Female
Humans
Male
Middle Aged
Receptor Tyrosine Kinase-like Orphan Receptors
Wnt-5a Protein
Young Adult