Chetty Chandramu, Bhoopathi Praveen, Joseph Pushpa, Chittivelu Subramanyam, Rao Jasti S, Lakka Sajani
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
Mol Cancer Ther. 2006 Sep;5(9):2289-99. doi: 10.1158/1535-7163.MCT-06-0169.
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.
基质金属蛋白酶（MMP）是一组蛋白酶，在细胞外基质的降解和重塑过程中发挥正常的生理作用。它们在肿瘤进展的不同阶段也具有多种作用。在许多肿瘤中都观察到MMP水平升高；这些升高与侵袭性表型密切相关。MMP-2和MMP-9尤其参与癌症的侵袭和转移。目前，MMP抑制剂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，采用这种策略的临床试验疗效有限。一个主要问题是市售MMP抑制剂缺乏特异性。构建了一种表达针对MMP-2基因的小干扰RNA的腺病毒载体（Ad-MMP-2），以特异性抑制MMP-2的表达。评估了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。通过蛋白质印迹、明胶酶谱分析和逆转录聚合酶链反应测定，肺癌细胞感染Ad-MMP-2后，MMP-2蛋白、活性和转录水平均出现特异性下调。Ad-MMP-2抑制作用还减轻了肺癌的侵袭和迁移，并在体外减少了肿瘤细胞诱导的血管生成。在实验性转移性肺肿瘤模型中，用Ad-MMP-2治疗已形成的肿瘤可抑制小鼠皮下肿瘤生长和肺结节形成。腺病毒介导的针对MMP-2的RNA干扰对肺癌具有显著的治疗潜力，并且通过抑制血管生成发挥部分作用。
