title: Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer.
abstract: BACKGROUND
  Wnt factors control cell differentiation through semi-independent molecular cascades known as the beta-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood.
  
  
  RESULTS
  Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic.
  
  
  CONCLUSIONS
  Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.
authors.affiliation: Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Lara
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.forename: Covadonga
authors.initials: C
authors.lastname: Huidobro
authors.forename: Agustin F
authors.initials: AF
authors.lastname: Fernández
authors.forename: Angela
authors.initials: A
authors.lastname: Moncada-Pazos
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Obaya
authors.forename: Oscar
authors.initials: O
authors.lastname: Aguilera
authors.forename: José Manuel
authors.initials: JM
authors.lastname: González-Sancho
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
mesh_terms: D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D011401:Promoter Regions, Genetic; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics*; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D051153:Wnt Proteins; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors