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 Guo, Qian Tao

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2179-2192
Number of pages14
JournalCellular and Molecular Life Sciences
Volume71
Issue number11
DOIs
StatePublished - Jun 2014

Keywords

  • Carcinoma
  • Epigenetic
  • Methylation
  • ROR2
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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