Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer.
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.
Lara
Ester
E
Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain.
Calvanese
Vincenzo
V
Huidobro
Covadonga
C
Fernández
Agustin F
AF
Moncada-Pazos
Angela
A
Obaya
Alvaro J
AJ
Aguilera
Oscar
O
González-Sancho
José Manuel
JM
Sánchez
Laura
L
Astudillo
Aurora
A
Muñoz
Alberto
A
López-Otín
Carlos
C
Esteller
Manel
M
Fraga
Mario F
MF
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*
D051153:Wnt Proteins; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors