ROR1 and ROR2 play distinct and opposing roles in endometrial cancer

C E Henry; E Llamosas; B Daniels; A Coopes; K Tang; C E Ford

doi:10.1016/j.ygyno.2018.01.025

ROR1 and ROR2 play distinct and opposing roles in endometrial cancer

Gynecol Oncol. 2018 Mar;148(3):576-584. doi: 10.1016/j.ygyno.2018.01.025. Epub 2018 Feb 1.

Authors

C E Henry¹, E Llamosas¹, B Daniels², A Coopes¹, K Tang³, C E Ford⁴

Affiliations

¹ Gynaecological Cancer Research Group, Lowy Cancer Research Centre, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Australia.
² Medicines Policy Research Unit, Centre for Big Data Research in Health, Faculty of Medicine, University of New South Wales, Australia.
³ South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, Australia.
⁴ Gynaecological Cancer Research Group, Lowy Cancer Research Centre, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Australia. Electronic address: caroline.ford@unsw.edu.au.

PMID: 29395309
DOI: 10.1016/j.ygyno.2018.01.025

Abstract

Objective: In recent years, the Wnt signalling pathway and the ROR1 and ROR2 receptors have been implicated in a range of gynecological cancers. These receptors have been described as prospective therapeutic targets, and this study investigated such potential in an endometrial cancer context.

Method: Immunohistochemistry for ROR1 and ROR2 was performed in a patient cohort, and expression was correlated with clinicopathological parameters including type, stage, grade, myometrial invasion, lymphovascular involvement, patient age and survival. The functional role of these receptors in endometrial cancer was investigated via siRNA knockdown of ROR1 and ROR2 in three cell line models (KLE, RL95-2 and MFE-319). Effects on proliferation, adhesion, migration and invasion were measured.

Results: High ROR1 expression in patient samples correlated with worse overall survival (p = 0.0169) while high ROR2 expression correlated with better overall survival (p = 0.06). ROR1 knockdown in KLE cells significantly decreased proliferation (p = 0.047) and reduced migration and invasion. ROR2 knockdown in RL95-2 cells increased cell migration and invasion (p = 0.011). Double ROR1 and ROR2 knockdown in MFE-319 cells decreased adhesion and significantly increased cell migration (P = 0.008) and invasion (p < 0.001).

Conclusion: ROR1 and ROR2 play distinct roles in endometrial cancer. ROR1 may promote tumor progression, similar to its role in ovarian cancer, while ROR2 may act as a tumor suppressor in endometrioid endometrial cancer, similar to its role in colorectal cancer. With several ROR-targeting therapies currently in development and phase I clinical trials for other tumor types, this study supports the potential of these receptors as therapeutic targets for women with endometrial cancer.

Keywords: Endometrial cancer; ROR1; ROR2; Uterine cancer; Wnt signalling.

MeSH terms

Adult
Age Factors
Carcinoma, Endometrioid / genetics*
Carcinoma, Endometrioid / metabolism
Carcinoma, Endometrioid / pathology
Cell Adhesion / genetics
Cell Line, Tumor
Cell Movement / genetics*
Cell Proliferation / genetics*
Cohort Studies
Endometrial Neoplasms / genetics*
Endometrial Neoplasms / metabolism
Endometrial Neoplasms / pathology
Female
Gene Knockdown Techniques
Humans
Immunohistochemistry
Middle Aged
Molecular Targeted Therapy
Myometrium
Neoplasm Grading
Neoplasm Invasiveness / genetics
Neoplasm Staging
Prognosis
RNA, Small Interfering
Receptor Tyrosine Kinase-like Orphan Receptors / genetics*
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Survival Rate
Wnt Signaling Pathway

Substances

RNA, Small Interfering
ROR1 protein, human
ROR2 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors