Downregulation of laminin α4 chain expression inhibits glioma invasion in vitro and in vivo
Downregulation of laminin α4 chain expression inhibits glioma invasion in vitro and in vivo
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DOI：
10.1002/ijc.21102
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发表时间：
2005-10-20
影响因子：
6.4
通讯作者：
Ohnishi, T
中科院分区：
文献类型：
--
作者：
Nagato, S;Nakagawa, K;Ohnishi, T
层粘连蛋白家族是细胞外基质的结构成分，在促进浸润性肿瘤细胞的运动方面起着至关重要的作用。我们研究了层粘连蛋白α4链，层粘连蛋白-8、-9和-14的一个子集，在人脑胶质瘤细胞的运动和侵袭活动中的作用。所有恶性胶质瘤细胞株表达的层粘连蛋白α4和β1链比表达β2链的更多，表明这些细胞主要表达层粘连蛋白-8亚型。将层粘连蛋白α4链的反义寡核苷酸(AS-Ln-α4)导入胶质瘤细胞，可下调层粘连蛋白A4的表达。AS-Ln-α4还能显著抑制胶质瘤细胞的黏附和迁移。此外，与转染正义寡核苷酸(S-Ln-α4)的细胞相比，转染AS-Ln-A4的细胞的侵袭力显著降低。事实上，当胶质瘤球体被植入大鼠脑片中时，AS-Ln-Alpha4转基因细胞未能侵入周围的正常脑组织。此外，脑内注射AS-Ln-α4基因的胶质瘤细胞可形成非侵袭性肿瘤，而注射S-Ln-α4基因的细胞可导致脑组织的弥漫性侵袭。这些结果表明，主要是层粘连蛋白-8对人脑胶质瘤细胞的侵袭活动是必不可少的；因此，一种新的治疗策略可以针对该分子来治疗恶性胶质瘤患者。(C)2005年Wilol-Liss，Inc.
The laminin family is a structural constituent of the extracellular matrix that plays an essential role in promoting the motility of infiltrative tumor cells. We investigated the role of laminin alpha 4 chain, a subset of laminin-8, -9 and -14, in the motile and invasive activities of human glioma cells. All malignant glioma cell lines examined expressed more mRNA for the laminin alpha 4 and beta 1 chains than for the beta 2 chain, indicating that these cells predominantly express the laminin-8 isoform. Introducing an antisense oligonucleotide for laminin alpha 4 chain (AS-Ln-alpha 4) into the glioma cells resulted in downregulation of laminin a4 expression. AS-Ln-alpha 4 also significantly suppressed glioma cell adhesion and migration. Furthermore, invasiveness was significantly reduced in cells transfected with AS-Ln-a4 compared to those transfected with the sense oligonucleotide (S-Ln-alpha 4). Indeed, when glioma spheroids were implanted into rat brain slices, AS-Ln-alpha 4-transfected cells failed to invade surrounding normal brain tissues. In addition, intracerebral injection of glioma cells transfected with AS-Ln-alpha 4 into nude mice resulted in the formation of a noninvasive tumor, whereas injection of cells transfected with S-Ln-alpha 4 resulted in diffuse invasion of brain tissue. These results suggest that mainly laminin-8 is essential for the invasive activity of human glioma cells; thus, a novel therapeutic strategy could target this molecule to treat patients with malignant glioma. (c) 2005 Wilol-Liss, Inc.