Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Neuro Oncol. 2010 Jan;12(1):58-70. doi: 10.1093/neuonc/nop013. Epub 2009 Dec 23.
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.
人恶性脑胶质瘤细胞的特征是局部侵袭。在本研究中，我们研究了骨桥蛋白（OPN）在源自 IV 级肿瘤的人神经胶质瘤细胞侵袭性中的作用。我们发现这些细胞系中 OPN 的表达水平与基质金属蛋白酶-2（MMP-2）表达和细胞侵袭潜能平行。当 U87MG 神经胶质瘤细胞（OPN 表达水平较高）被特异性短发夹 RNA 稳定转染以敲低 OPN 表达时，MMP-2 分泌、细胞侵袭性和植入脑中的肿瘤生长显著降低。相反，在 GBM-SKH 神经胶质瘤细胞（OPN 表达水平较低）中强制表达 OPN 增加了 MMP-2 的分泌，增强了细胞侵袭性，并增加了啮齿动物异种移植模型中的肿瘤生长。OPN 的表达与波形蛋白表达增加和神经胶质纤维酸性蛋白表达减少有关。用 5-氮杂-2'-脱氧胞苷（5-aza-dC）处理神经胶质瘤细胞可浓度依赖性地抑制 OPN 的表达。5-aza-dC 对 OPN 表达的抑制与 MMP-2 分泌、波形蛋白表达、细胞侵袭、血管内渗和肿瘤生长减少有关。这些数据表明，OPN 可能在调节神经胶质瘤细胞的细胞侵袭中发挥重要作用，并且 5-aza-dC 可能作为人类神经胶质瘤的治疗剂。
