Over-expression of cyclin D1 induces glioma invasion by increasing matrix metalloproteinase activity and cell motility.

In order to define the role of cyclin D1 in the progression of malignant glioma, cells over-expressing cyclin D1 were constructed (a-1 cells). They exhibited significantly increased invasiveness as compared with mock-transfected cells. Since cellular invasion is thought to depend on extracellular-matrix degradation, we determined whether cyclin-D1 expression modifies the activity of matrix metalloproteinases (MMPs). Increased gelatinolytic activity of latent type MMP-2 (proMMP-2) and active MMP-2 was observed in a-1 cells. Moreover, cyclin-D1 expression was associated with increased activation of proMMP-9 through MMP-3. Wound assays showed an increase of cell motility in a-1 cells. Cyclin-D1 expression was found to be associated with up-regulation of Rac1, which modulates the formation of ruffling membranes and cell motility. Our results show that cyclin D1 may modulate invasive ability by increasing MMP activity and cell motility, and suggests a novel function of cyclin D1 in the progression of malignant gliomas. Copyright 1999 Wiley-Liss, Inc.