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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 |
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| Authors: | Lili Li Jianming Ying Xin Tong Lan Zhong Xianwei Su Tingxiu Xiang Xingsheng Shu Rong Rong Lei Xiong Hongyu Li Anthony T C Chan Richard F Ambinder Yajun Guo Qian Tao |
| Institution: | 1. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong 2. PLA General Hospital Cancer Center, 28 Fuxing Road, Beijing, 100853, China 3. Cancer Institute, Second Military Medical University, Shanghai, China 4. The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 5. Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA |
| 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. |
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