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Tumor necrosis factor alpha delivers exogenous inflammation-related microRNAs to recipient cells with functional targeting capabilities
Molecular Therapy ( IF 12.4 ) Pub Date : 2022-07-05 , DOI: 10.1016/j.ymthe.2022.06.017
Yuechao Zhao 1 , Tan Zhang 2 , Xuelian Shen 3 , Aixue Huang 1 , Hui Li 1 , Lin Wang 1 , Xuemei Liu 1 , Xuejun Wang 4 , Xiang Song 4 , Shengqi Wang 4 , Jie Dong 1 , Ningsheng Shao 1
Affiliation  

Tumor necrosis factor alpha (TNF-α) is a critical pro-inflammatory cytokine in a wide range of tumors and infectious diseases. This study showed for the first time that TNF-α could specifically bind to certain intracellular or circulating inflammation-related microRNAs both in vitro and in vivo. The binding sites of TNF-α to microRNAs are located at the N-terminal of TNF-α and the 3′-GGUU motif of microRNAs. TNF-α could deliver exogenous unmodified single-stranded microRNAs into recipient cells through the TNF-α receptors (TNFRs) and stabilize them from being degraded by RNase in cells. Exogenous miR-146a or let-7c delivered into HCT116 cells by TNF-α could escape from lysosomes and specifically downregulate their target genes and then affect cell proliferation and migration in vitro, as well as tumorigenesis in vivo. Based on the above findings, the concept of “non-conjugated ligand-mediated RNA delivery (ncLMRD)” was proposed, which may serve as a promising strategy for therapeutic microRNA delivery in the future.



中文翻译:

肿瘤坏死因子 α 将外源性炎症相关 microRNA 传递至具有功能性靶向能力的受体细胞

肿瘤坏死因子 α (TNF-α) 是多种肿瘤和传染病中重要的促炎细胞因子。这项研究首次表明TNF-α在体外体内都可以特异性结合某些细胞内或循环炎症相关的microRNA 。TNF-α 与 microRNA 的结合位点位于 TNF-α 的 N 端和 microRNA 的 3'-GGUU 基序。TNF-α可以通过TNF-α受体(TNFR)将外源未修饰的单链microRNA递送到受体细胞中,并稳定它们不被细胞中的RNase降解。TNF-α将外源性miR-146a或let-7c递送至HCT116细胞中,可以逃离溶酶体并特异性下调其靶基因,进而影响细胞体外增殖和迁移以及体内肿瘤发生。基于上述发现,提出了“非缀合配体介导的RNA递送(ncLMRD)”的概念,这可能成为未来治疗性microRNA递送的一种有前途的策略。

更新日期:2022-07-05
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