Cellular and Molecular Life Sciences

, Volume 71, Issue 11, pp 2179–2192 | Cite as

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

  • 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 GuoEmail author
  • Qian TaoEmail author
Research Article


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.


Epigenetic Tumor suppressor ROR2 Methylation Carcinoma 



We thank Drs. George Tsao, Sun Young Rha, Bert Vogelstein, and Michael Obster for some cell lines, DSMZ (German Collection of Microorganisms and Cell Cultures) for the KYSE cell lines (Shimada et al., Cancer 69: 277-284, 1992). This study was supported by grants from National Natural Science Foundation (No. 81372898 and 81172582), Hong Kong RGC (GRF # 474710), and Group Research Schemes of The Chinese University of Hong Kong.

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

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Supplementary material 1 (PDF 9909 kb)
18_2013_1485_MOESM2_ESM.doc (88 kb)
Supplementary material 2 (DOC 88 kb)
18_2013_1485_MOESM3_ESM.doc (52 kb)
Supplementary material 3 (DOC 51 kb)


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Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Lili Li
    • 1
  • Jianming Ying
    • 1
  • Xin Tong
    • 2
    • 3
  • Lan Zhong
    • 1
  • Xianwei Su
    • 1
  • Tingxiu Xiang
    • 4
  • Xingsheng Shu
    • 1
  • Rong Rong
    • 1
  • Lei Xiong
    • 1
  • Hongyu Li
    • 1
  • Anthony T. C. Chan
    • 1
  • Richard F. Ambinder
    • 5
  • Yajun Guo
    • 2
    • 3
    Email author
  • Qian Tao
    • 1
    • 5
    Email author
  1. 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 SciencesThe Chinese University of Hong Kong and CUHK Shenzhen Research InstituteShatinHong Kong
  2. 2.PLA General Hospital Cancer CenterBeijingChina
  3. 3.Cancer InstituteSecond Military Medical UniversityShanghaiChina
  4. 4.The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  5. 5.Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer CenterJohns Hopkins School of MedicineBaltimoreUSA

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