Anti-matrix metalloproteinase-9 DNAzyme decreases tumor growth in the MMTV-PyMT mouse model of breast cancer.
Anti-matrix metalloproteinase-9 DNAzyme decreases tumor growth in the MMTV-PyMT mouse model of breast cancer.
复制标题
DOI：
10.1186/bcr3385
复制
发表时间：
2013-02-13
期刊：
影响因子：
--
通讯作者：
Pourmotabbed T
中科院分区：
文献类型：
--
作者：
Hallett MA;Teng B;Hasegawa H;Schwab LP;Seagroves TN;Pourmotabbed T
尽管在诊断、手术技术和化疗方面不断改进，乳腺癌患者仍然被癌症转移所困扰。肿瘤细胞的增殖、侵袭和转移至少部分是通过肿瘤和基质细胞产生的中性基质金属蛋白酶(MMPs)降解基底膜来实现的。有证据表明，基质金属蛋白酶-9在乳腺肿瘤细胞的侵袭和转移中起重要作用。DNAzyme或催化寡核苷酸是一类新型的基因靶向分子，它结合和切割特定的mRNA，导致蛋白质表达减少。在体外和体内用MDA-MB-231细胞和MMTV-PYMT转基因乳腺癌小鼠模型评价了抗基质金属蛋白酶-9脱氧核酶(AM9D)在乳腺癌治疗中的应用。在MMTV-PYMT转基因小鼠自发形成的乳腺肿瘤中，瘤内注射裸AM9D，每周1次，连续4周。用荧光标记的DNAzyme测定了DNAzyme的体内外稳定性。AM9D特异性地抑制了MDA-MB-231细胞中基质金属蛋白酶-9的表达，使其侵袭性降低了43%。在MMTV-PYMT转基因小鼠中，每周一次的瘤内治疗足以显著降低肿瘤生长速度和最终肿瘤负荷，且具有剂量依赖性和统计学意义(P<；0.05)。肿瘤生长的减少与治疗后肿瘤组织中基质金属蛋白酶-9蛋白的减少有关。与对照组和未治疗的肿瘤相比，接受AM9D治疗的肿瘤血管较少，且含有更多的凋亡细胞。这些结果表明，AM9D靶向和下调基质金属蛋白酶-9可能被证明是有效的治疗乳腺癌肿瘤生长和侵袭。
Despite continued improvements in diagnosis, surgical techniques, and chemotherapy, breast cancer patients are still overcome by cancer metastasis. Tumor cell proliferation, invasion and metastasis are mediated, at least in part, through degradation of basement membrane by neutral matrix metalloproteinases (MMP) produced by tumor and stromal cells. Evidence suggests that MMP-9 plays a significant role in breast tumor cell invasion and metastasis. DNAzymes or catalytic oligonucleotides are new classes of gene targeting molecules that bind and cleave a specific mRNA, resulting in decreased protein expression. The application of anti-MMP-9 DNAzyme (AM9D) for the treatment of primary and metastatic breast cancer was evaluated in vitro and in vivo using MDA-MB-231 cells and the MMTV-PyMT transgenic breast cancer mouse model. Spontaneously developed mammary tumors in MMTV-PyMT transgenic mice were treated intratumorally with naked AM9D, once a week for 4 weeks. The stability of DNAzyme was determined in vitro and in vivo using fluorescently labeled DNAzyme. AM9D specifically inhibited expression of MMP-9 in MDA-MB-231 cells resulting in reduced invasive property of these cells by 43%. Weekly intratumoral treatment of spontaneously developed mammary tumors in MMTV-PyMT transgenic mice was sufficient to significantly reduce the rate of tumor growth and final tumor load in a dose dependent and statistically significant manner (P < 0.05). This decrease in tumor growth was correlated with decreased MMP-9 protein production within the treated tumor tissues. Tumors treated with AM9D were also less vascularized and contained more apoptotic cells compared to control and untreated tumors. These results show that targeting and down regulation of MMP-9 by AM9D could prove useful as a therapy against breast carcinoma tumor growth and invasion.
登录
查看更多内容
DOI：
10.1186/bcr1530
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fantozzi A;Christofori G
通讯作者：
Christofori G
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
5.7
作者：
Almholt, Kasper;Juncker-Jensen, Anna;Romer, John
通讯作者：
Romer, John
影响因子：
16.6
作者：
LIOTTA, LA;RAO, CN;WEWER, UM
通讯作者：
WEWER, UM
影响因子：
3.2
作者：
Chantrain, CF;DeClerck, YA;McNamara, G
通讯作者：
McNamara, G