Adenovirus-mediated small interfering RNA against matrix metalloproteinase-2 suppresses tumor growth and lung metastasis in mice
Adenovirus-mediated small interfering RNA against matrix metalloproteinase-2 suppresses tumor growth and lung metastasis in mice
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DOI：
10.1158/1535-7163.mct-06-0169
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发表时间：
2006-09-01
影响因子：
5.7
通讯作者：
Lakka, Sajani
中科院分区：
文献类型：
--
作者：
Chetty, Chandramu;Bhoopathi, Praveen;Lakka, Sajani
基质金属蛋白酶（MMP）是一组具有正常生理作用的降解和重塑细胞外基质的蛋白酶。它们在肿瘤发展的不同阶段也有多种作用。在许多肿瘤中观察到MMPs水平升高；这些增加与侵袭性表型密切相关。MMP-2和MMP-9特别参与癌症的侵袭和转移。MMP抑制剂目前正在临床前模型和临床试验中作为多种癌症的治疗药物进行测试。迄今为止，使用这种策略的临床试验效果有限。一个主要的问题是市售的MMP抑制剂缺乏特异性。构建了一种表达小干扰RNA （Ad-MMP-2）的腺病毒载体，特异性抑制MMP-2的表达。研究了Ad-MMP-2对A549肺癌细胞侵袭、血管生成、肿瘤生长和转移的影响。通过Western blotting、明胶酶谱和逆转录- pcr检测，肺癌细胞感染Ad-MMP-2后，MMP-2蛋白、活性和转录均出现特异性下调。Ad-MMP-2抑制还可以减轻肺癌的侵袭和迁移，并减少肿瘤细胞诱导的体外血管生成。在实验性转移性肺肿瘤模型中，用Ad-MMP-2治疗已建立的肿瘤可抑制小鼠s.c.肿瘤的生长和肺结节的形成。腺病毒介导的RNA干扰对MMP-2具有显著的治疗潜力，并通过抑制血管生成发挥部分作用。
Matrix metalloproteinases (MMP) are a group of proteinases that have normal physiologic roles degrading and remodeling the extracellular matrix. They also have multiple roles in different stages of tumor progression. Elevated levels of MMPs have been observed in many tumors; these increases have a strong association with the invasive phenotype. MMP-2 and MMP-9 are particularly involved in cancer invasion and metastasis. MMP inhibitors are currently being tested as therapeutic agents for a number of cancers in both preclinical models and in clinical trials. To date, clinical trials using this strategy have had limited efficacy. A major concern is the lack of specificity of commercially available MMP inhibitors. An adenoviral vector expressing small interfering RNA against the MMP-2 gene (Ad-MMP-2) was constructed to specifically inhibit MMP-2 expression. The effect of Ad-MMP-2 on invasion, angiogenesis, tumor growth, and metastasis of A549 lung cancer cell was evaluated. Ad-MMP-2 infection of lung cancer cells showed specific down-regulation of MMP-2 protein, activity, and transcription as determined by Western blotting, gelatin zymography, and reverse transcription-PCR. Ad-MMP-2 inhibition also mitigated lung cancer invasion and migration, and reduced tumor cell-induced angiogenesis in vitro. In an experimental metastatic lung tumor model, treatment of established tumors by Ad-MMP-2 inhibited s.c. tumor growth and formation of lung nodules in mice. Adenoviral-mediated RNA interference against MMP-2 has significant therapeutic potential for lung cancer and exerts some of this effect by inhibiting angiogenesis.