Abstract
Simple SummaryEndometrial cancer is one of the fastest rising cancers in women. The Wnt signalling receptor ROR2 has been shown to play distinct roles in regards to tumorigenesis in different tumour types. The aim of this study was to investigate the role of ROR2 in endometrial cancer and to determine if ROR2 expression is epigenetically regulated. Through the analyses of publicly available TCGA and GEO datasets, low ROR2 expression was correlated with unfavourable outcome and reduced overall survival of endometrial cancer patients. In addition, we observed epigenetic repression of ROR2 expression in endometrial cancer cell lines and patient samples. Ectopic expression of ROR2 in vitro inhibited the invasive ability of high grade serous endometrial cancer cells. Therefore, we concluded that ROR2 plays a tumour suppressor role in endometrial cancer and appears to be a diagnostic or therapeutic candidate.The Wnt signalling receptor ROR2 has been identified as a possible therapeutic target in numerous cancers; however, its exact role remains unclear. The aim of this study was to investigate the role of ROR2 in endometrial cancer (EC) and the potential mechanism associated with its altered expression. The association between ROR2 mRNA expression levels and clinicopathological parameters, including overall survival (OS), in EC was analysed in The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) cohort and GEO dataset GSE17025. Four EC cell lines (KLE, MFE-296, Ishikawa and ARK-1) and eight clinical EC samples were analysed for ROR2 methylation via Combined Bisulphite Restriction Analysis (COBRA) and bisulphite genomic sequencing (BGS). In addition, the functional effects of ROR2 overexpression were investigated in Ishikawa and ARK-1 cells following ectopic ROR2 expression. ROR2 promoter methylation or reduced ROR2 expression were both found to correlate with shorter OS, high grade and serous subtype in the TCGA-UCEC and GEO datasets. ROR2 was epigenetically silenced by promoter methylation in both patient samples and cell lines. A significant correlation between ROR2 expression levels and promoter methylation was observed in patient samples (r = −0.797, p = 0.018). ROR2 restoration in ARK-1 significantly decreased invasion ability, with associated changes in epithelial-mesenchymal transition (EMT) markers. ROR2 plays a tumour-suppressor role in EC and is epigenetically suppressed with the development of disease. It may represent a diagnostic or therapeutic candidate for EC.
Highlights
Endometrial cancer (EC) is one of the fastest rising cancers worldwide, with more than 380,000 new cases diagnosed in 2018 [1]
Expression and Methylation Status of ROR2 is Associated with Overall Survival in an EC Cohort
We explored whether ROR2 expression or methylation was associated with stage or grade
Summary
Endometrial cancer (EC) is one of the fastest rising cancers worldwide, with more than 380,000 new cases diagnosed in 2018 [1]. It was historically classified into two subgroups: estrogen-dependent Type I (mainly endometrioid subtype) and estrogen independent Type II (other subtypes such as serous, clear cell) [2]. Survival outcomes for high grade, metastatic endometrioid EC as well as highly aggressive subtypes, remain poor [8] This is largely due to the fact that most clinically aggressive subtypes are diagnosed at late stages, and respond poorly to the available treatment options. The rapidly rising incidence of aggressive non-endometrioid EC [9] has necessitated the identification of new biomarkers to predict EC progression, and target therapeutically
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