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

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 G 0 -G 1 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]

SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD

“…Both TIMP-1 and MMP-9 play an important role in cellular senescence, proliferation, and apoptosis, which are the pivotal contributing factors in driving the progression of COPD/emphysema (1,13,27,30,37,38,42,45,49). This provides a possibility that the protection against experimental emphysema by SIRT1 is due to reduced cellular senescence and apoptosis via redressing of TIMP-1/MMP-9 imbalance in mouse lungs by a mechanism involving dampening the senescence-associated secretory phenotype.…”

Downregulation of matrix metalloproteinase 9 by small interfering RNA inhibits the tumor growth of ovarian epithelial carcinoma in vitro and in vivo

“…These results imply that silencing MMP-9 is an effective method for the treatment of ovarian cancer. MMP-9 is one of the most important metalloproteases and is critical in regulating ECM dissolution, activating growth factors as well as initiating intracellular signaling leading to tumor progression and metastasis (26)(27)(28)(29). Several studies have demonstrated that inhibiting the activities of MMP-9 by RNAi resulted in apoptosis in melanoma cells (15), malignant meningioma cells (27) and medulloblastoma cells (28).…”

Matrix metalloproteinase‐9 interplays with the IGFBP2–IGFII complex to promote cell growth and motility in astrocytomas

“…Short interfering RNA (siRNA) was recently shown to be an effective method for inhibiting the expression of a specific gene in human cells, and current published data suggest antitumor potential effects of this technique (Tong et al, 2005). Indeed, a siRNA sequence of human MMP-9 was shown to inhibit medulloblastoma cell growth and invasion both in vitro and in vivo (Rao et al, 2007). Furthermore, simultaneous downregulation of uPAR and MMP-9 expression by means of RNA interference dramatically reduced glioblastoma growth, invasion, and angiogenesis in both in vitro and in vivo models (Lakka et al, 2005).…”