Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma.

The mechanism underlying the progression of normal esophageal mucosa to esophageal adenocarcinoma (EAC) remains elusive. WNT5A is a non-canonical 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 EAC. Analysis of WNT5A and ROR2 expression patterns in healthy controls, Barrett's and EAC patients' esophageal clinical specimens as well as in various esophageal cell lines demonstrated a ROR2-overexpression in EAC tissues compared to Barrett's and healthy mucosa, while WNT5A expression was found significantly down-regulated towards EAC 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. Additionally, ROR2-knockdown alone abolished cell proliferation and weakened the migration properties of OE33 cells. These findings support an early dysregulation of the non-canonical WNT5A/ROR2 pathway in the pathogenesis of EAC, with the loss of WNT5A expression together with the ROR2 overexpression to be consistent with tumor promotion. Implications: The dysregulation of WNT5A/ROR2 non-canonical WNT-signaling in Barrett-associated esophageal adenocarcinoma introduces possible prognostic markers and novel targets for tailored therapy of this malignancy.