WIF1 (WNT inhibitory factor 1)

2012-04-01   Irene Vassallo , Monika E Hegi 

Laboratory of Brain Tumor Biology, Genetics, Lausanne University Hospital, Lausanne, Switzerland


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Figure 1. WIF1 genomic context.


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Figure 2. A) WIF1 gene structure. Transcription unit 71007 bp, mRNA 2304 bp. B) Structure of human WIF1 promoter.


The human WIF1 gene is located on the chromosome 12q14.2 from 65444404 bp to 65515346 bp (from pter). It is oriented on the minus strand and comprises 10 exons spanning 71007 bp of genomic DNA. The first and the 10th exons are partially composed by untranslated regions.


The mRNA produced is 2304 bp long. The promoter region of WIF1 has been cloned and studied by Reguart et al. and its structure is shown in Figure 2B (Reguart et al., 2004). Regulatory elements in the WIF1 promoter comprise a TATA box and binding sites of the transcription factors: Engrailed, E2F, GLI-Kruppel, NF-κB, and MYC, as visualized in Figure 2B. The CpG island located upstream of the WIF1 transcriptional start site is prone to aberrant methylation in various tumor types. Hypermethylation of this region has been found to be responsible for WIF1 downregulation, suggestive of tumor suppressor properties in different cancer types.


No pseudogene known so far.


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Figure 3. WIF1 protein domains.


WIF1 is a protein of 379 aminoacids, composed of a signal peptide for extracellular secretion, a WIF domain, five EGF repeats and a hydrophilic C terminus (Figure 3).
The WIF domain is responsible for the binding with some of the WNT ligands (3a, 4, 5a, 7a, 9a, 11) and to olfactomedin 1, a protein involved in neuronal differentiation (Hsieh et al., 1999).


In development WIF1 starts to be produced during somitogenesis and maintains its expression in adults mainly in the lung, heart, and at the cartilage-mesenchyme interface (data derived from Xenopus, zebrafish and mouse).


WIF1 is an extracellular secreted protein.


WIF1 is a secreted WNT inhibitor that works by sequestering soluble Wnt proteins. It prevents the interaction between WNT morphogens and their specific receptors (Figure 4). WIF1 has been shown to bind to agonists of both, the canonical and the non-canonical WNT pathway. In contrast to other inhibitors like DKKs that can inhibit only the β-catenin dependent pathway, WIF1 can block the activation of both the canonical and the non-canonical WNT signaling pathway (Kawano and Kypta, 2003). Recently has been shown by Malinauskas et al. that WIF1 has a modular mechanism of inhibition. The WIF domain is responsible for the binding of WNT1 with WNT ligands and the five EGF-like domains seems to be partially involved in the extracellular localization of WIF1. The essential formation of gradients of WNT morphogens during development is mediated by interaction of the EGF-like domains and some glycosaminoglycans, namely heparin and heparan sulfate (Malinauskas et al., 2011).
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Figure 4. WIF1 inhibition mechanism.


The WIF1 gene is conserved in
- P. troglodytes (WIF1)
- C. lupus (WIF1)
- M. musculus (WIF1)
- R. norvegicus (WIF1)
- G. gallus (WIF1)
- D. rerio (WIF1)
- D. melanogaster (shf)



WIF1 is rarely mutated in human cancer.


According to COSMIC (Catalogue of Somatic Mutations in Cancer) only 6 samples over 1103 sequenced human cancer specimens show mutations that lead to amminoacid missense substitution.
Genomic deletions of the region where WIF1 is located have instead been reported for 10% of glioblastoma samples (Lambiv et al., 2011).

Implicated in

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Cervical cancer
WIF1 is downregulated by promoter hypermethylation in 87.5% of primary cervical cancer. Peritumoral WIF1 gene transfer induces apoptosis and inhibits growth and invasion (Ramachandran et al., 2011).
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WIF1 silencing is mediated by both deletion (7/69, 10%) and promoter hypermethylation (29/110, 26%). WIF1 re-expression abolishes tumorigenicity of glioblastoma cell lines potentially by inducing senescence (Lambiv et al., 2011).
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Primary non-small-cell lung carcinoma (NSCLC)
WIF1 is frequently downregulated and this downregulation is correlated with WIF1 promoter hypermethylation (Mazieres et al., 2004).
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Hypermethylation of the WIF1 promoter is found in the majority of osteosarcoma cell lines tested and it correlates with WIF1 mRNA downregulation (Rubin et al., 2010).
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Hepatocellular carcinoma (HCC)
WIF1 is frequently downregulated through promoter hypermethylation (Deng et al., 2010).
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WIF-1 promoter methylation was reported from 73.9% of mesothelioma tissues and in 100% of tested mesothelioma cell lines (Kohno et al., 2010).
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Renal cell carcinoma (RCC)
WIF-1 is downregulated by promoter methylation and when re-expressed induces apoptosis in RCC cells (Kawakami et al., 2009).
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Bladder cancer
Epigenetic inactivation of WIF1 in bladder cancer deregulates WNT pathway activation. WIF1 re-expression induces a G1-arrest via p27 and p21 accumulation (Tang et al., 2009; Urakami et al., 2006).
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Esophageal adenocarcinoma (EAC)
Epigenetic alteration of WIF1 is an early event in the carcinogenesis of EAC. Its suggested to be involved in the progression from Barretts esophagus (BE) to EAC thus WIF1 hypermethylation is proposed to be used as a diagnostic and predictive marker for increased EAC risk in BE patients. (Clément et al., 2008).
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Gastrointestinal cancers
WIF-1 expression has been reported to be downregulated in 80.0% of esophageal, 74.2% of gastric, 82.0% of colorectal, and 75% of pancreatic cancer tissues. WIF1 silencing, mediated by hypermethylation, is proposed to be an early event in colorectal carcinogenesis (Taniguchi et al., 2005).
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Breast cancer
67% of the investigated invasive breast adenocarcinoma (Stages II or III) shows aberrant WIF1 promoter methylation (Ai et al., 2006).
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Salivary gland pleomorphic adenoma
WIF1 is rearranged resulting in a HMGA2/WIF1 fusion transcript. In consequence of this fusion WIF1 that in normal salivary gland tissue is highly expressed becomes downregulated. On the contrary, HMGA2 that in normal tissue is not expressed is strongly upregulated (Queimado et al., 2007).


Pubmed IDLast YearTitleAuthors
165012522006Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer.Ai L et al
180051972008Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.Clément G et al
201197132010Epigenetic silencing of WIF-1 in hepatocellular carcinomas.Deng Y et al
102013741999A new secreted protein that binds to Wnt proteins and inhibits their activities.Hsieh JC et al
198876052009Functional significance of Wnt inhibitory factor-1 gene in kidney cancer.Kawakami K et al
127757742003Secreted antagonists of the Wnt signalling pathway.Kawano Y et al
205966292010Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma.Kohno H et al
216423722011The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.Lambiv WL et al
217434552011Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.Malinauskas T et al
152564372004Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer.Mazieres J et al
171716862007WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors.Queimado L et al
220023052012Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo.Ramachandran I et al
153517262004Cloning and characterization of the promoter of human Wnt inhibitory factor-1.Reguart N et al
201973882010Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma.Rubin EM et al
191745562009WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells.Tang Y et al
160071172005Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers.Taniguchi H et al
164284762006Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway.Urakami S et al

Other Information

Locus ID:

NCBI: 11197
MIM: 605186
HGNC: 18081
Ensembl: ENSG00000156076


dbSNP: 11197
ClinVar: 11197
TCGA: ENSG00000156076


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Wnt signaling pathwayKEGGhsa04310
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Negative regulation of TCF-dependent signaling by WNT ligand antagonistsREACTOMER-HSA-3772470


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD24980784
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD24980784


Pubmed IDYearTitleCitations
193077282009Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice.93
241183802013HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway.88
164284762006Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway.69
157357432005Constitutive activation of the Wnt/beta-catenin signalling pathway in acute myeloid leukaemia.64
160071172005Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers.60
197733812009Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer.60
170122252007Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes.58
217434552011Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.54
166090232006Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection.53
201973882010Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma.53


Irene Vassallo ; Monika E Hegi

WIF1 (WNT inhibitory factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-04-01

Online version: http://atlasgeneticsoncology.org/gene/44085/wif1-(wnt-inhibitory-factor-1)