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

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.

High expression of ROR2 in cancer cell correlates with unfavorable prognosis in colorectal cancer

“…This result is consistent with previous reports showing that ROR2 mRNA is highly upregulated in cancer cell lines [31,36]. To further confirm this analysis, TMAs were constructed using primary CRC specimens.…”

Tenascin C regulates proliferation and differentiation processes during embryonic retinogenesis and modulates the de-differentiation capacity of Müller glia by influencing growth factor responsiveness and the extracellular matrix compartment

“…Recently, it has been demonstrated that Pax6 regulates the expression of the alternatively spliced isoforms of Tnc (von Holst et al, 2007). The Wnt signaling pathway constitutes an additional cascade regulating cell cycle progression, proliferation, apoptosis and differentiation of retinal precursor cells in a stage-dependent manner (Lara et al, 2010). Another investigated effector was the neurogenic basic helix-loophelix (bHLH) transcription factor Mash1, which is expressed by retinal precursor cells and is involved in cell fate specification (Akagi et al, 2004).…”

“…Investigations of a Tnc À / À mouse strain (Forsberg et al, 1996;Saga et al, 1992) revealed subtle alterations in non-neural and neural tissues, resulting in several neurological defects, inhibition of regeneration/plasticity and de-regulated morphogenesis (Evers et al, 2002;Faissner, 1997;Fukamauchi et al, 1996;Fukamauchi et al, 1997;Garcion et al, 2004;Irintchev et al, 2005;Jones and Jones, 2000a). Immunohistochemical analysis revealed that Tnc is expressed in the retina in a spatiotemporal pattern (Klausmeyer et al, 2007;Lara et al, 2010). Investigations concerning the influence of Tnc during retinogenesis remained an outstanding question.…”

Epigenetics and Pancreatic Cancer: The Role of Nutrigenomics

“…Regulation of specific genes in a subset of regulatory pathways has been identified to be disrupted in pancreatic cancer and modulated by dietary agents (78). These pathways involve apoptosis, DNA damage control, K-ras signaling, JNK signalings, invasion, Hedgehog signaling, Wnt-Notch signaling, TGF-ß, and regulation of the G1/S phase transition (79)(80)(81). The dietary agent curumin, a yellow spice found in both turmeric and curry powder, inhibits JNK, COX2, NF-kappaB, STAT3 and AP-1 activation (82) through epigenetic mechanisms.…”