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

Molecular Cancer, Jun 2010

Background 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. 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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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. - 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)


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Ester Lara, Vincenzo Calvanese, Covadonga Huidobro, Agustin F Fernández, Ángela Moncada-Pazos, Álvaro J Obaya, Oscar Aguilera, José González-Sancho, Laura Sánchez, Aurora Astudillo, Alberto Muñoz, Carlos López-Otín, Manel Esteller, Mario F Fraga. Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer, Molecular Cancer, 2010, pp. 170, 9, DOI: 10.1186/1476-4598-9-170