Journal
ONCOTARGET
Volume 7, Issue 38, Pages 62425-62438Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11515
Keywords
astrocytes; glioma; invasion; IL-6; MMP14
Categories
Funding
- National Natural Science Foundation of China [81572478]
- Shandong Provincial Outstanding Medical Academic Professional Program
- Special Foundation for Taishan Scholars [ts20110814, tshw 201502056]
- Fundamental Research Funds of Shandong University
- Department of Science & Technology of Shandong Province [2015GGE27101, 2015GSF118074, 2015ZDXX0801A01]
- China Postdoctoral Science Fund [2014M551916]
- Shandong Provincial Foundation for Distinguished Young Scholars [BS2012YY016]
- University of Bergen, Norway
- Norwegian Centre for International Cooperation in Education (SIU) [UTF-2014/10047]
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The brain microenvironment has emerged as an important component in malignant progression of human glioma. However, astrocytes, the most abundant glial cells in the glioma microenvironment, have as yet a poorly defined role in the development of this disease, particularly with regard to invasion. Here, we co-cultured human astrocytes with human glioma cell lines, U251 and A172, in an in vitro transwell system in order to ascertain their influence on migration and invasion of gliomas. mRNA and protein expression assays were subsequently used to identify candidate proteins mediating this activity. Astrocytes significantly increased migration and invasion of both U251 and A172 cells in migration and invasion (plus matrigel) assays. Membrane type 1 matrix metalloproteinase (MMP14) originating from glioma cells was identified in qRT-PCR as the most highly up-regulated member of the MMP family of genes (similar to 3 fold, p < 0.05) in this system. A cytokine array and ELISA were used to identify interleukin-6 (IL-6) as a highly increased factor in media collected from astrocytes, especially under co-culture conditions. IL-6 was also the key cytokine inducing cytomembrane MMP14 expression, the active form of MMP14, in glioma cells. Knockdown of MMP14 with siRNA led to decreased migration and invasion. Taken together, our results indicated that cytomembrane MMP14 was induced by IL-6 secreted from astrocytes, thereby enhancing the migration and invasion of glioma cells through activation of MMP2. Therefore, this IL-6 and MMP14 axis between astrocytes and glioma cells may become a potential target for treatment of glioma patients.
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