title: Van-Gogh-like 2 antagonises the canonical WNT pathway and is methylated in colorectal cancers.
abstract: BACKGROUND
  Aberrant activation of the canonical WNT signaling is a feature of colorectal cancer (CRC). Van-Gogh-like 2 (VANGL2) belongs to the non-canonical WNT pathway whose activation inhibits canonical WNT signaling. In this study, we investigated the role of VANGL2 and its epigenetic regulation in CRC.
  
  
  METHODS
  Van-Gogh-like 2 expression and promoter methylation after 5-aza-2'-deoxycytidine (5-aza) treatment were evaluated in CRC cells. DNA samples from 418 sporadic CRCs were tested for VANGL2 promoter methylation and microsatellite instability (MSI). Proliferation, colony formation and activation of the WNT pathway were tested in cells after VANGL2 overexpression.
  
  
  RESULTS
  Van-Gogh-like 2 mRNA was significantly higher in 5-aza-treated RKO, LOVO and SW48, whereas no differences were found in SW480. Van-Gogh-like 2 was fully methylated in RKO, SW48, HCT116, DLD1 and Caco2; partially methylated in LOVO, LS174T and SW837; and unmethylated in SW480, SW620 and HT29. Higher expression of VANGL2 mRNA was found in the unmethylated cell lines. In CRC specimens (8.93% MSI), methylated VANGL2 was associated with MSI, higher grade, proximal colon location and BRAF mutation. Van-Gogh-like 2 overexpression in SW480 significantly decreased proliferation, colony formation and β-catenin levels.
  
  
  CONCLUSIONS
  Van-Gogh-like 2 is frequently methylated in MSI-CRCs with BRAF mutation and may act as a tumour suppressor gene, counteracting WNT/β-catenin signaling.
authors.affiliation: Department of Internal Medicine, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA.
authors.forename: G
authors.initials: G
authors.lastname: Piazzi
authors.forename: M
authors.initials: M
authors.lastname: Selgrad
authors.forename: M
authors.initials: M
authors.lastname: Garcia
authors.forename: C
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: L
authors.initials: L
authors.lastname: Fini
authors.forename: P
authors.initials: P
authors.lastname: Bianchi
authors.forename: L
authors.initials: L
authors.lastname: Laghi
authors.forename: L
authors.initials: L
authors.lastname: D'Angelo
authors.forename: P
authors.initials: P
authors.lastname: Paterini
authors.forename: P
authors.initials: P
authors.lastname: Malfertheiner
authors.forename: P
authors.initials: P
authors.lastname: Chieco
authors.forename: C R
authors.initials: CR
authors.lastname: Boland
authors.forename: F
authors.initials: F
authors.lastname: Bazzoli
authors.forename: L
authors.initials: L
authors.lastname: Ricciardiello
mesh_terms: D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018938:Caco-2 Cells; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D053842:Microsatellite Instability; D009154:Mutation; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C468513:VANGL2 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D000077209:Decitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D001374:Azacitidine