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.
Highlights
Gliomas are the most common primary brain tumors, and among them, glioblastomas are the most frequent, accounting for approximately 50% of all gliomas, but are the most aggressive subtype, with a mean survival of 16 months [1]
We have previously showed that WNK2 downregulation induces Rac1 activation, leading to increased migration, an important cellular alteration involved in the invasion process [16]
Due to the pivotal role of Matrix metalloproteinases (MMPs) in extracellular matrix (ECM) degradation, and to the invasion process, together with the documented association between MMP2 and MMP9 expression and severity of disease in gliomas [20, 21], we interrogated whether the WNK2 methylation status was associated with MMP2 and MMP9 activity levels in a panel of eight glioma cell lines
Summary
Gliomas are the most common primary brain tumors, and among them, glioblastomas are the most frequent, accounting for approximately 50% of all gliomas, but are the most aggressive subtype, with a mean survival of 16 months [1]. 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 patient death [2]. MMPs are able to degrade all components of the extracellular matrix, eliminating the physical barrier to cell movement, and creating the route to the invading cells [4]
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