Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo.
Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo.
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MUC16启动子的转录控制促进促卵泡激素肽缀合的shRNA纳米颗粒介导的体内卵巢癌抑制
DOI：
10.1080/10717544.2018.1451934
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发表时间：
2018-11
期刊：
影响因子：
6
通讯作者：
Xu CJ
中科院分区：
文献类型：
--
作者：
Zhang MX;Hong SS;Cai QQ;Zhang M;Chen J;Zhang XY;Xu CJ
摘要卵巢癌是妇科恶性肿瘤中死亡率最高的恶性肿瘤。尽管手术和化疗取得了进展，但高死亡率并没有显著降低。基因治疗显示了治疗潜力，但在临床应用之前必须解决几个关键问题。为了使非癌组织中的毒性最小化，将肿瘤特异性配体缀合至载体以增加药物递送的选择性。促卵泡激素（FSH）受体在正常和癌组织中的表达模式为卵巢癌的高选择性药物递送提供了机会。此外，肿瘤特异性启动子可以有条件地调节肿瘤或正常组织中治疗基因的表达。由于MUC 16/CA 125在大多数卵巢癌中过表达，因此MUC 16启动子可能是驱动卵巢癌局部基因表达的潜在工具。我们筛选了MUC 16启动子序列，构建了MUC 16启动子驱动的gro-α shRNA质粒载体。通过FSH肽缀合的纳米颗粒将载体特异性地递送到卵巢癌细胞中。预测的启动子序列与TAAA重复序列显示出较高的转录活性。含有MUC 16启动子驱动的gro-α shRNA和FSH肽的纳米颗粒复合物能够减少卵巢癌细胞中gro-α蛋白的分泌，并在荷卵巢癌裸鼠模型中阻断肿瘤生长，而没有明显的毒性作用。我们的研究提供了一种新的基因递送系统，使用MUC 16启动子触发器和FSH肽介导的主动靶向卵巢癌，该系统可能是一个有前途的战略，为特定的基因治疗交付。
Abstract Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.
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影响因子：
4
作者：
Hong S;Zhang X;Chen J;Zhou J;Zheng Y;Xu C
通讯作者：
Xu C
影响因子：
--
作者：
Morgado M;Sutton MN;Simmons M;Warren CR;Lu Z;Constantinou PE;Liu J;Francis LL;Conlan RS;Bast RC Jr;Carson DD
通讯作者：
Carson DD
影响因子：
3.9
作者：
Suh DH;Kim M;Kim K;Kim HJ;Lee KH;Kim JW
通讯作者：
Kim JW
影响因子：
2.9
作者：
Higashi M;Yokoyama S;Yamamoto T;Goto Y;Kitazono I;Hiraki T;Taguchi H;Hashimoto S;Fukukura Y;Koriyama C;Mataki Y;Maemura K;Shinchi H;Jain M;Batra SK;Yonezawa S
通讯作者：
Yonezawa S
影响因子：
37.3
作者：
Felder M;Kapur A;Gonzalez-Bosquet J;Horibata S;Heintz J;Albrecht R;Fass L;Kaur J;Hu K;Shojaei H;Whelan RJ;Patankar MS
通讯作者：
Patankar MS