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MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway

2007; American Association for Cancer Research; Volume: 67; Issue: 10 Linguagem: Inglês

10.1158/0008-5472.can-07-0380

1538-7445

Jasti S. Rao, Praveen Bhoopathi, Chandramu Chetty, Meena Gujrati, Sajani S. Lakka,

Cell Adhesion Molecules Research

Abstract The involvement of matrix metalloproteinases (MMP) has been suggested in cellular mechanisms leading to medulloblastoma, the most common malignant brain tumor in children. A significant association of the expression levels of MMP-9 with survival and M stage suggests that patients with medulloblastoma metastatic disease at diagnosis may benefit from the anti-MMP therapy. Here, we have evaluated the tumorigenicity of medulloblastoma cells after infection with an adenovirus containing a 21-bp short interfering RNA sequence of the human MMP-9 gene (Ad-MMP-9). Infection of Daoy medulloblastoma cells with Ad-MMP-9 reduced MMP-9 activity and protein levels compared with parental and Ad-SV controls. Ad-MMP-9 decreased the number of viable Daoy cells in a concentration-dependent manner. Fluorescence-activated cell sorting analysis indicated that Ad-MMP-9 infection caused a dose-dependent cell cycle arrest in the G0-G1 phase. Ad-MMP-9–induced cell cycle arrest seems to be mediated by the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway and the cell cycle inhibitor p16INK4a and is phenotypically indistinguishable from senescence. Ad-MMP-9 treatment inhibited medulloblastoma tumor growth in an intracranial model and was mediated by up-regulation of p16 expression. These studies validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of medulloblastoma. [Cancer Res 2007;67(10):4956–64]