Open Access Research

Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer

Ester Lara1, Vincenzo Calvanese1, Covadonga Huidobro2, Agustin F Fernández2, Ángela Moncada-Pazos3, Álvaro J Obaya3, Oscar Aguilera4, José Manuel González-Sancho4, Laura Sánchez5, Aurora Astudillo5, Alberto Muñoz4, Carlos López-Otín3, Manel Esteller6 and Mario F Fraga1*

Author Affiliations

1 Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain

2 Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006-Oviedo, Spain

3 Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain

4 Instituto de Investigaciones Biomédica Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, E-28029 Madrid, Spain

5 Banco de Tumores. Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, 33006-Oviedo, Spain

6 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

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Molecular Cancer 2010, 9:170  doi:10.1186/1476-4598-9-170

Published: 30 June 2010



Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-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.


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.


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.