title: WIF1 re-expression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the lncRNA MALAT1.
abstract: Glioblastoma is the most aggressive primary brain tumor in adults and due to the invasive nature cannot be completely removed. The WNT inhibitory factor 1 (WIF1), a secreted inhibitor of WNTs, is systematically downregulated in glioblastoma and acts as strong tumor suppressor. The aim of this study was the dissection of WIF1-associated tumor-suppressing effects mediated by canonical and non-canonical WNT signaling. We found that WIF1 besides inhibiting the canonical WNT pathway selectively downregulates the WNT/calcium pathway associated with significant reduction of p38-MAPK (p38-mitogen-activated protein kinase) phosphorylation. Knockdown of WNT5A, the only WNT ligand overexpressed in glioblastoma, phenocopied this inhibitory effect. WIF1 expression inhibited cell migration in vitro and in an orthotopic brain tumor model, in accordance with the known regulatory function of the WNT/Ca(2+) pathway on migration and invasion. In search of a mediator for this function differential gene expression profiles of WIF1-expressing cells were performed. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA and key positive regulator of invasion, emerged as the top downregulated gene. Indeed, knockdown of MALAT1 reduced migration in glioblastoma cells, without effect on proliferation. Hence, loss of WIF1 enhances the migratory potential of glioblastoma through WNT5A that activates the WNT/Ca(2+) pathway and MALAT1. These data suggest the involvement of canonical and non-canonical WNT pathways in glioblastoma promoting key features associated with this deadly disease, proliferation on one hand and invasion on the other. Successful targeting will require a dual strategy affecting both canonical and non-canonical WNT pathways.
authors.affiliation: Neurosurgery (NCH), Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Clinical Neurosciences, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), Epalinges, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Vassallo
authors.affiliation: Department of Neurological Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zinn
authors.affiliation: Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Lai
authors.affiliation: Neurosurgery (NCH), Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Clinical Neurosciences, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), Epalinges, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Rajakannu
authors.affiliation: Neurosurgery (NCH), Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Clinical Neurosciences, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), Epalinges, Switzerland.
authors.forename: M-F
authors.initials: MF
authors.lastname: Hamou
authors.affiliation: Neurosurgery (NCH), Lausanne University Hospital (CHUV), Lausanne, Switzerland.|Department of Clinical Neurosciences, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV), Epalinges, Switzerland.
authors.forename: M E
authors.initials: ME
authors.lastname: Hegi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C557041:MALAT1 long non-coding RNA, human; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; C485569:WIF1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein