Lakka Sajani S, Rajan Mannari, Gondi Christopher, Yanamandra Niranjan, Chandrasekar Nirmala, Jasti Sushma L, Adachi Yoshiaki, Siddique Khawar, Gujrati Meena, Olivero William, Dinh Dzung H, Kouraklis Gregory, Kyritsis Athanassios P, Rao Jasti S
Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois, Peoria 61656, USA.
Oncogene. 2002 Nov 14;21(52):8011-9. doi: 10.1038/sj.onc.1205894.
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.
基质金属蛋白酶9（MMP - 9）在生理和病理过程中的细胞迁移和侵袭中起主要作用。我们之前的研究表明，MMP - 9水平升高与人类胶质瘤肿瘤进展相关。在本研究中，我们评估了一种腺病毒的能力，该腺病毒含有一段与人类MMP - 9基因5'端呈反义方向的528 bp cDNA序列（Ad - MMP - 9AS），在体外和体内模型中抑制人类胶质母细胞瘤细胞系SBN19的侵袭性和迁移能力。与空载体或Ad - CMV感染的细胞相比，用Ad - MMP - 9AS感染胶质瘤细胞可使MMP - 9酶活性降低约90%。在球体和基质胶试验中，相对于Ad - CMV感染的对照，用Ad - MMP - 9AS感染的胶质母细胞瘤细胞的迁移和侵袭受到显著抑制。向裸鼠颅内注射用Ad - MMP - 9AS感染的SNB19细胞未产生肿瘤。然而，将Ad - MMP - 9AS构建体注射到裸鼠皮下的U87MG肿瘤中会导致肿瘤生长消退。这些结果支持了以下理论，即腺病毒介导的反义方向MMP - 9基因传递具有治疗胶质瘤的潜力。
