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- Title
Epigenetic identification of receptor tyrosine kinase-like orphan receptor 2 as a functional tumor suppressor inhibiting β-catenin and AKT signaling but frequently methylated in common carcinomas.
- Authors
Li, Lili; Ying, Jianming; Tong, Xin; Zhong, Lan; Su, Xianwei; Xiang, Tingxiu; Shu, Xingsheng; Rong, Rong; Xiong, Lei; Li, Hongyu; Chan, Anthony; Ambinder, Richard; Guo, Yajun; Tao, Qian
- Abstract
Through subtraction of tumor-specific CpG methylation, we identified receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a candidate tumor suppressor gene (TSG). ROR2 is a specific receptor or co-receptor for WNT5A, involved in canonical and non-canonical WNT signaling, with its role in tumorigenesis controversial. We characterized its functions and related cell signaling in common carcinomas. ROR2 was frequently silenced by promoter CpG methylation in multiple carcinomas including nasopharyngeal, esophageal, gastric, colorectal, hepatocellular, lung, and breast cancers, while no direct correlation of ROR2 and WNT5A expression was observed. Ectopic expression of ROR2 resulted in tumor suppression independent of WNT5A status, through inhibiting tumor cell growth and inducing cell cycle arrest and apoptosis. ROR2 further suppressed epithelial-mesenchymal transition and tumor cell stemness through repressing β-catenin and AKT signaling, leading to further inhibition of tumor cell migration/invasion and increased chemo-sensitivity. Thus ROR2, as an epigenetically inactivated TSG, antagonizes both β-catenin and AKT signaling in multiple tumorigenesis. Its epigenetic silencing could be a potential tumor biomarker and therapeutic target for carcinomas.
- Subjects
PROTEIN-tyrosine kinase inhibitors; PROTEIN receptors; EPIGENETICS; PROTEIN kinase B; CELLULAR signal transduction; TUMOR suppressor genes; METHYLATION
- Publication
Cellular & Molecular Life Sciences, 2014, Vol 71, Issue 11, p2179
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-013-1485-z