Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer
Molecular Cancer
REepseairgchenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer
Ester Lara 0
Vincenzo Calvanese 0
Covadonga Huidobro 2
Agustin F Fernndez 2
ngela Moncada-Pazos 1
lvaro J Obaya 1
Oscar Aguilera 5
Jos Manuel Gonzlez-Sancho 5
Laura Snchez 4
Aurora Astudillo 4
Alberto Muoz 5
Carlos Lpez-Otn 1
Manel Esteller 3
Mario F Fraga 0
0 Department of Immunology and Oncology, National Center for Biotechnology , CNB-CSIC, Cantoblanco, Madrid E-28049 , Spain
1 Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo , 33006-Oviedo , Spain
2 Cancer Epigenetics Laboratory, Instituto Universitario de Oncologia del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo , 33006-Oviedo , Spain
3 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Spain
4 Banco de Tumores. Instituto Universitario de Oncologia del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo , 33006-Oviedo , Spain
5 Instituto de Investigaciones Biomedica Alberto Sols, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid , E-28029 Madrid , Spain
Background: Wnt factors control cell differentiation through semi-independent molecular cascades known as the 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.
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Introduction
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]. Accordingly, ROR2 mutations in humans result in
dominant brachydactyly type B and Robinow syndrome
[4], two syndromes of altered development characterised
by short stature, brachydactyly, segmental defects of the
spine and dysmorphic facial appearance [5].
ROR2 exerts its role in cell differentiation primarily
through the Wnt signalling pathway [6]. This pathway is
comprised of a number of extracellular effectors,
membrane proteins, intracellular signal transducers and
nuclear gene regulators that transmit extracellular signals
to the nucleus as precise instructions for regulating
specific genes [7]. When -catenin participates in this
cascade, the signalling pathway is known as canonical Wnt.
Wnt effectors can also induce -catenin-independent
signals that make up the non-canonical Wnt signalling
pathway. Within the Wnt signalling pathway, the primary role
of ROR2 is to mediate WNT5A signals in a complex
manner that is still unclear. ROR2 was initially shown to
mediate WNT5A-dependent inhibition of canonical Wnt
signalling downstream of -catenin stabilisation in 293
cells, at the level of TCF-mediated transcription [8].
ROR2 was subsequently shown to mediate
WNT5Adependent JNK activation in regulating convergent
extension movements in Xenopus gastrulation [9], and is
also known to enhance WNT1 and antagonise WNT3
activities in osteoblastic cells [10]. In the H441 lung
carcinoma cell line, ROR2 positively modulates
Wnt3a-activated canonical signalling [11].
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 is overexpressed in oral [12] and renal cancer [13],
and in osteosarcoma [14]. ROR2 overexpression activates
JNK, a component of the non-canonical Wnt pathway,
and has pro-tumourigenic effects [13,14].
ROR2 also mediates inhibition of the
-catenin-dependent Wnt signalling pathway [8,10,15]. Paradoxically, the
aberrant epigenetic repression of other Wnt inhibitors
such as WIF-1, DKK1, SFRP1 and SFRP2 directly
promotes tumourigenesis in colon cancer cells by promoting
constitutive Wnt signalling [7,16-18]. Indeed, the ROR (...truncated)