Establishment of a novel therapy for glioma invasion by antisense inhibition of the targeting molecule.

为了阐明胶质瘤侵袭的分子机制，我们研究了laminin-8在脑肿瘤中的表达，并探讨了反义抑制laminin-8对胶质瘤细胞迁移和侵袭的影响。laminin-8蛋白和mRNA在恶性胶质瘤中高表达，尤其是在弥漫性侵袭的胶质母细胞瘤中。laminin-8（α4亚基）的反义表达在不影响胶质瘤细胞生长的情况下，显著抑制胶质瘤细胞的体外迁移和侵袭。此外，在大鼠脑切片模型和肿瘤接种模型中，反义蛋白laminin-8均能显著抑制胶质瘤细胞的侵袭。反义抑制laminin-8导致胶质瘤细胞中肌动蛋白应激纤维的形成较弱，但不影响Rac和Cdc42的表达。这些结果表明，基因抑制laminin-8可能通过抑制局灶性粘连的形成来抑制胶质瘤细胞的运动。

In order to clarify the molecular mechanism of glioma invasion, we studied an expression of laminin-8 in brain tumors and investigated an effect of antisense inhibition of laminin-8 on migration and invasion of glioma cells. The protein and mRNA of laminin-8 were highly expressed in malignant gliomas, particulary in glioblastomas showing diffuse invasion. Antisense of laminin-8(α4 subunit) markedly inhibited the glioma cell migration and invasion in vitro without affecting the cell growth. In addtion, antisense of laminin-8 significantly inhibited the glioma cell invasion in both a rat brain slice model and a tumor-inoculated model. Antisense inhibition of laminin-8 resulted in weak formation of actin stress fibers in glioma cells but did not affect the expression of Rac and Cdc42. These results suggest that gene suppression of laminin-8 may inhibit the glioma cell motility through the inhibition of formation of focal adhesion.