title: Silencing of the tumor suppressor gene WNK2 is associated with upregulation of MMP2 and JNK in gliomas.
abstract: Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2. Also, WNK2 inhibited JNK, a process associated with decreasing levels of MMP2. Thus, WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential.
authors.affiliation: ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga 4710-057, Portugal.|ICVS/3B's - PT -Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal.
authors.forename: Angela Margarida
authors.initials: AM
authors.lastname: Costa
authors.affiliation: ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga 4710-057, Portugal.|ICVS/3B's - PT -Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal.
authors.forename: Filipe
authors.initials: F
authors.lastname: Pinto
authors.affiliation: ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga 4710-057, Portugal.|ICVS/3B's - PT -Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal.
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.affiliation: INEB-Institute of Biomedical Engineering, Porto 4150-180, Portugal.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Oliveira
authors.affiliation: Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisbon 1649-016, Portugal.|BioFig-Center of Biodiversity, Functional and Integrative Genomics, Lisbon 1649-016, Portugal.
authors.forename: Peter
authors.initials: P
authors.lastname: Jordan
authors.affiliation: ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga 4710-057, Portugal.|ICVS/3B's - PT -Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP 14784-400, Brazil.
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C523482:WNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2