Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer
Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer
复制标题
用于胰腺癌中 plectin-1 靶向 miRNA-9 递送的嵌合肽超分子纳米颗粒
DOI：
10.7150/thno.38327
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发表时间：
2020
期刊：
影响因子：
12.4
通讯作者：
Chen Wei
中科院分区：
文献类型：
--
作者：
Wu Ying;Tang Yuexiao;Xie Shangzhi;Zheng Xiaoxiao;Zhang Shufen;Mao Jiayan;Wang Baoming;Hou Yuerou;Hu Liqiang;Chai Kequn;Chen Wei
胰腺导管腺癌（PDAC）是一种高致死性疾病，预后差.对MicroRNA（miRNAs）在疾病中的作用的深入了解，特别是在癌症中，使得miRNAs成为新治疗方法的有吸引力的工具和靶标。研究方法：在这里，我们采用了一种新的嵌合肽超分子纳米颗粒递送系统，用于在体外和胰腺癌患者来源的异种移植物（PDX）模型中递送plectin-1（PL-1）靶向的PDAC特异性miR-9。采用RT-PCR和免疫组化方法检测eIF 5A 2的表达情况。用mRFP-GFP-LC 3荧光显微镜和Western blot检测自噬。进行荧光素酶报告基因测定以阐明miR-9/eIF 5A 2轴的调节作用。结果如下：PL-1/miR-9纳米复合物通过下调eIF 5A 2表达来显著改善阿霉素的抗癌作用，从而抑制体内PDAC治疗中的自噬并诱导凋亡。从机制上讲，miR-9通过结合其3 '-非翻译区（3'-UTR）直接靶向eIF 5A 2转录物，以降低PDAC细胞中eIF 5A 2的表达水平和分泌蛋白。结论：PL-1/miR-9纳米粒可作为一种具有肿瘤靶向性的新型抗癌策略，miR-9/eIF 5A 2可作为一种新的潜在治疗靶点用于未来针对人PDAC的协同治疗。
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Methods: Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery in vitro and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis. Results: PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy in vivo. Mechanistically, miR-9 directly targets the eIF5A2 transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells. Conclusion: PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.