Abstract
BackgroundWnt 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.ResultsHere 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.ConclusionsOur 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.
Highlights
The receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane protein that belongs to a conserved family of tyrosine kinase receptors involved in many developmental processes, including chondrogenesis [1], osteoblastogenesis [2] and neural differentiation [3]
To study the possible aberrant epigenetic regulation of ROR2 in colon cancer, we used bisulphite sequencing of multiple clones to determine the methylation status of a ROR2 promoter DNA region of 315 bp that spans the ROR2 transcriptional start point in healthy colon tissue, in vitro-growing colonocytes and eight colon cancer cell lines (HCT116, SW480, LOVO, HT29, HCT15, DLD1, COLO205 and RKO) (Figure 1A). This showed that the ROR2 promoter was completely unmethylated in non-tumourigenic colon primary tissues and in vitro-growing colonocytes, whilst it was densely hypermethylated in most cancer cell lines analysed (HT29, HCT15, DLD1, COLO205 and RKO)
We report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane protein that participates in Wnt signalling, is frequently repressed by aberrant promoter hypermethylation in human colon cancer
Summary
The receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane protein that belongs to a conserved family of tyrosine kinase receptors involved in many developmental processes, including chondrogenesis [1], osteoblastogenesis [2] and neural differentiation [3]. ROR2 exerts its role in cell differentiation primarily through the Wnt signalling pathway [6]. The Wnt signalling pathway is central to cell differentiation and cancer. Genetic and epigenetic alterations of components of the canonical Wnt signalling pathway are a primary mechanism of colon cancer development [7]. ROR2 overexpression activates JNK, a component of the non-canonical Wnt pathway, and has pro-tumourigenic effects [13,14]. Wnt factors control cell differentiation through semi-independent molecular cascades known as the βcatenin-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, the underlying molecular mechanisms are poorly understood
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