1Department of Neuropathology, Tianjin Neurological Institute,Tianjin Medical University General Hospital; Key Laboratory of Post-trauma Neuro-repair and Regeneration in the Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin 300052, China
2Département de Chimie et Biochimie, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada
3Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China

Abstract 

The matrix-degrading metalloproteinases (MMPs),particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas.
In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA (pcDNA-ASMMP9), which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4- to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex (AS-MMP-9-treated group), subcutaneous injection of endostatin (endostatin-treated group), or both (combined therapy group). Mice treated with pcDNA (empty vector)-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas.

Keywords

matrix-degrading metalloproteinase 9; antisense MMP-9 RNA; cell proliferation; malignant glioma cells

[SpringerLink]