MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.
MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.
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DOI：
10.1016/j.canlet.2015.06.002
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发表时间：
2015-09
期刊：
影响因子：
9.7
通讯作者：
I. Ulasov;A. Borovjagin;N. Kaverina;Brett Schroeder;N. Shah;B. Lin;A. Baryshnikov;C. Cobbs
中科院分区：
文献类型：
--
作者：
I. Ulasov;A. Borovjagin;N. Kaverina;Brett Schroeder;N. Shah;B. Lin;A. Baryshnikov;C. Cobbs
MMP 14（MT 1-MMP）是一种细胞外基质的细胞膜相关蛋白酶，其生物学作用从血管生成到细胞增殖和存活不等。我们最近发现胶质瘤患者脑肿瘤中MMP 14的表达水平与疾病进展直接相关。通过使用基因沉默作为实验方法，我们发现MMP 14敲低降低促血管生成因子如VEGF和IL 8的产生，从而抑制神经胶质瘤肿瘤中的血管生成。尽管MMP 14下调的临床相关性及其对人类胶质瘤治疗的可能意义尚不清楚，但我们观察到在用表达MMP 14的shRNA的CRAd感染的小鼠颅内胶质瘤异种移植物中，MMP 14下调后动物存活率显著改善。我们进一步发现，通过用CRAd-S-5/3和Marimastat（一种金属蛋白酶的化学抑制剂）联合治疗，神经胶质瘤中MMP 14的下调增强了由有复制能力的腺病毒引起的促血管生成因子的抑制。我们还证明了通过纤维修饰的腺病毒载体将MMP 14靶向shRNA递送到胶质瘤细胞中有效地抑制了它们在体外和体内的增殖。因此，我们的数据表明，抑制肿瘤中MMP 14的表达与胶质瘤病毒治疗相结合，可以有效地用于通过减少促血管生成因子的产生来抑制胶质瘤肿瘤的血管生成和新血管形成。
MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down-regulation and its possible implications for glioma therapy in humans remain unclear, we observed a significant improvement in animal survival upon down-regulation of MMP14 in murine intracranial glioma xenografts infected with MMP14 shRNA-expressing CRAd. We further found that down-regulation of MMP14 in gliomas by combinational treatment with CRAd-S-5/3 and Marimastat, a chemical inhibitor of metalloproteinases, augments suppression of pro-angiogenic factors, caused by the replication-competent adenovirus. We also demonstrated that delivery of MMP14-targeting shRNA by a fiber-modified adenoviral vector to the glioma cells effectively suppresses their proliferationin vitroandin vivo. Thus our data indicate that inhibition of MMP14 expression in tumors in combination with glioma virotherapy could be effectively utilized to suppress angiogenesis and neovascularization of glioma tumors by decreasing production of pro-angiogenic factors.