title: The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.
abstract: Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.
authors.affiliation: Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, Lausanne University Hospital (CHUV BH19-110), 46, rue du Bugnon, Lausanne 1011, Switzerland.
authors.forename: Wanyu L
authors.initials: WL
authors.lastname: Lambiv
authors.forename: Irene
authors.initials: I
authors.lastname: Vassallo
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Tal
authors.initials: T
authors.lastname: Shay
authors.forename: Annie-Claire
authors.initials: AC
authors.lastname: Diserens
authors.forename: Anjan
authors.initials: A
authors.lastname: Misra
authors.forename: Burt
authors.initials: B
authors.lastname: Feuerstein
authors.forename: Anastasia
authors.initials: A
authors.lastname: Murat
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hamou
authors.forename: Davide
authors.initials: D
authors.lastname: Sciuscio
authors.forename: Raphael
authors.initials: R
authors.lastname: Burger
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C485569:WIF1 protein, human