Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion

Abstract

Matrix metalloproteinase 9 (MMP-9) is known to play a major role in cell migration and invasion in both physiological and pathological processes. Our previous work has shown that increased MMP-9 levels are associated with human glioma tumor progression. In this study, we evaluated the ability of an adenovirus containing a 528 bp cDNA sequence in antisense orientation to the 5' end of the human MMP-9 gene (Ad-MMP-9AS) to inhibit the invasiveness and migratory capacity of the human glioblastoma cell line SBN19 in in vitro and in vivo models. Infection of glioma cells with Ad-MMP-9AS reduced MMP-9 enzyme activity by approximately 90% compared with mock-or Ad-CMV-infected cells. Migration and invasion of glioblastoma cells infected with Ad-MMP-9AS were significantly inhibited relative to Ad-CMV-infected controls in spheroid and Matrigel assays. Intracranial injections of SNB19 cells infected with Ad-MMP-9AS did not produce tumors in nude mice. However, injecting the Ad-MMP-9AS construct into subcutaneous U87MG tumors in nude mice caused regression of tumor growth. These results support the theory that adenoviral-mediated delivery of the MMP-9 gene in the antisense orientation has therapeutic potential for treating gliomas.

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

“…In the present study, we directly exposed LN229 cells to exogenous human purified MMP-9, and showed that MMP-9 acts as a stimulator of both astrocytoma cell growth and motility. Similar results were indirectly reported by Lakka et al (2002), who showed that the downregulation of MMP-9 expression reduced astrocytoma cell growth, motility, and invasion. In addition to direct MMP-9-induced stimulation of cell growth and motility, we showed that the proteolysis of the IGFBP2-IGFII complex by MMP-9 caused a dramatic increase in both cell growth and cell motility, suggesting that MMP-9 and the IGF system may collaborate to promote astrocytoma aggressiveness.…”

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

“…Although its role in metastatic tumor cell growth is still unclear, increased MMP expression is frequently accompanied by tumor metastasis and suppression of MMP expression could be used as a growth inhibitory treatment to prevent tumor metastasis. 23,27,28 When pshHIF-1a was administered to tumor-bearing mice by the hydrodynamics-based procedure, a significant reduction in the number of tumor cells was observed (Figure 6a). This result indicates that HIF-1a expression in either tumor cells or hepatic normal cells or in both types of cells plays an important role in tumor progression.…”

Gelatinase-mediated migration and invasion of cancer cells

“…MMP-2, but not MMP-9 was found to be necessary for glomerular mesangial cell proliferation and differentiation (Turck et al, 1996). Similarly, adenoviral delivery of antisense mRNA of MMP-9 effectively suppressed tumor xenograft growth in vivo (Lakka et al, 2002). Small interfering RNAs have also been used to specifically silence MMP-9.…”