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.
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.
authors.affiliation: 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.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.forename: Lan
authors.initials: L
authors.lastname: Zhong
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Shu
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051057:Proto-Oncogene Proteins c-akt