Silencing of WNK2 is associated with upregulation of MMP2 and JNK in gliomas
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Angela Margarida Costa1,2, Filipe Pinto1,2, Olga Martinho1,2, Maria José Oliveira3, Peter Jordan4,5, Rui Manuel Reis1,2,6
1ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga 4710-057, Portugal
2ICVS/3B’s - PT -Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
3INEB-Institute of Biomedical Engineering, Porto 4150-180, Portugal
4Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisbon 1649-016, Portugal
5BioFig-Center of Biodiversity, Functional and Integrative Genomics, Lisbon 1649-016, Portugal
6Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP 14784-400, Brazil
Rui Manuel Reis, e-mail: [email protected]
Keywords: WNK2, MMP2, JNK, gliomas, invasion
Received: July 16, 2014 Accepted: November 25, 2014 Published: December 22, 2014
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.
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