Silencing of the tumor suppressor gene WNK2 is associated with upregulation of MMP2 and JNK in gliomas

Gliomas are the most common and malignant brain tumors.. Due to their high infiltrative and invasive capacity into adjacent tissues, these tumors are extremely difficult to be completely resected during surgery, leading to tumor recurrence, and ultimately patient death. Therefore, the knowledge of the molecular mechanisms associated with cancer invasion process is crucial to prevent this phenomena, thus increasing the survival of gliomas patients. ,

A research group from ICVS (Minho University), together with members from INSA, and INEB, contributed to the identification of WNK2 as a molecule involved in the regulation of the invasive process in gliomas.. In previous works, the same group had described that WNK2 is usually silenced in gliomas through promoter hypermethylation mechanisms. In the present study, published in Oncotarget, the researchers described for the first time that the WNK2 silencing is associated with increased activity of JNK kinase. JNK, in turn, regulates the production and activity of the metalloproteinase MMP2, a protein associated with extracellular matrix degradation, a crucial process cancer invasion. Furthermore, the researchers found an association between WNK2 expression and the inflammatory and pro-oncogenic interleukin IL-6 expression.  

Authors and Affiliations:

Angela Margarida Costa ^1,2, Filipe Pinto ^1,2, Olga Martinho ^1,2, Maria José Oliveira ³, Peter Jordan ^4,5, Rui Manuel Reis ^1,2,6,*

¹ ICVS-Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal;

² ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal;

³ INEB-Institute of Biomedical Engineering, Porto, Portugal;

⁴ Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, Lisbon, Portugal;

⁵ BioFig-Center of Biodiversity, Functional and Integrative Genomics, Lisbon, Portugal;

⁶ Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil

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.

Journal: Oncotarget

Link: http://www.ncbi.nlm.nih.gov/pubmed/25596741