Human astrocytes secrete IL-6 to promote glioma migration and invasion through upregulation of cytomembrane MMP14.
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 (~ 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.
Department of Otolaryngology, Qilu Hospital, Shandong University, Jinan, China.|Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.|Key Laboratory of Otolaryngology, Chinese Ministry of Health, Jinan, China.
Weiliang
W
Chen
Department of Otolaryngology, Qilu Hospital, Shandong University, Jinan, China.|Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.|Key Laboratory of Otolaryngology, Chinese Ministry of Health, Jinan, China.
Tongliang
T
Xia
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.
Donghai
D
Wang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.
Bin
B
Huang
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.
Peng
P
Zhao
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.|Department of Biomedicine, University of Bergen, Bergen, Norway.
Jian
J
Wang
Institute of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China.
Xun
X
Qu
Department of Neurosurgery, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, Jinan, China.
Xingang
X
Li
D000328:Adult; D001253:Astrocytes / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane; D002465:Cell Movement; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness
C508600:IL6 protein, human; D015850:Interleukin-6; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
IL-6; MMP14; astrocytes; glioma; invasion