Osteopontin regulates human glioma cell invasiveness and tumor growth in mice.
Human malignant glioma cells are characterized by local invasion. In the present study, we investigated the role of osteopontin (OPN) in the invasiveness of human glioma cells isolated from grade IV tumors. We found that the expression levels of OPN in these cell lines paralleled matrix metalloproteinase-2 (MMP-2) expression and cell invasiveness potential. When U87MG glioma cells (with a high-OPN expression level) were stably transformed with specific small hairpin RNA to knock down OPN expression, MMP-2 secretion, cell invasiveness, and tumor growth in implanted brains were dramatically reduced. Conversely, forced expression of OPN in GBM-SKH glioma cells (which expressed OPN at a low level) increased MMP-2 secretion, enhanced cell invasiveness, and increased tumor growth in a rodent xenograft model. Expression of OPN was associated with increased expression of vimentin and decreased expression of glial fibrillary acidic protein. Treatment of glioma cells with 5-aza-2'-deoxycytidine (5-aza-dC) suppressed OPN expression in a concentration-dependent manner. Suppression of OPN expression by 5-aza-dC was associated with reductions in MMP-2 secretion, vimentin expression, cell invasion, intravasation, and tumor growth. These data suggest that OPN may play important roles in regulating cell invasion in glioma cells and that 5-aza-dC may serve as a therapeutic agent for human gliomas.
Jan
Hsun-Jin
HJ
Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Lee
Chin-Cheng
CC
Shih
Yung-Luen
YL
Hueng
Dueng-Yuan
DY
Ma
Hsin-I
HI
Lai
Jing-Huei
JH
Wei
Hen-Wei
HW
Lee
Horng-Mo
HM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000077209:Decitabine; D004591:Electrophoresis, Polyacrylamide Gel; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D053495:Osteopontin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014746:Vimentin / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014746:Vimentin; D053495:Osteopontin; D000077209:Decitabine; D020778:Matrix Metalloproteinase 2; D001374:Azacitidine