欧洲槲寄生衍生的val-miR218对骨肉瘤的抑制作用。

Inhibition of osteosarcoma by European Mistletoe derived val-miR218.

作者信息

Xie Wenyan, Delebinski Catharina, Gürgen Dennis, Schröder Maik, Seifert Georg, Melzig Matthias F

机构信息

Institute of Pharmacy, Freie Universität Berlin, Berlin 14195, Germany.

Department of Pediatric Oncology/Hematology, Otto-Heubner-Centre for Pediatric and Adolescent Medicine (OHC), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin 13353, Germany.

出版信息

Extracell Vesicles Circ Nucl Acids. 2023 Jul 3;4(3):306-322. doi: 10.20517/evcna.2023.15. eCollection 2023.

DOI:10.20517/evcna.2023.15

PMID:39698025

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11651123/

Abstract

AIM

In recent years, there has been a growing interest in the therapeutic potential of plant-derived miRNAs, which have been considered new bioactive ingredients in medicinal plants. L., commonly used as an adjuvant cancer therapy in central Europe, contains a large number of miRNAs associated with human diseases such as cancer, cardiovascular diseases, and neurological disorders. This study aimed to investigate whether mistletoe miRNAs, specifically val-miR218, exert anti-cancer activity against osteosarcoma.

METHODS

The anti-cancer effects of miRNAs from L. were evaluated. The targets of val-miR218 were identified by RNA-seq. The mRNA and protein expression of the targets was confirmed by RT-qPCR and western blot analyses. The interaction between the val-miR218 and miRNA recognition elements (MREs) was validated by the dual-luciferase assay. The inhibitory effect of val-miR218 against osteosarcoma was investigated .

RESULTS

Among these abundant miRNAs in L., val-miR218 showed high potential anti-cancer effects against osteosarcoma. To clarify its molecular mechanism of action, we sequenced val-miR218 associated RNAs and their down-regulated RNAs. As a result, 61 genes were considered the direct targets of val-miR218. Interestingly, these targets were related to essential cellular functions such as cell cycle, DNA replication, and cell morphology, suggesting that val-miR218 significantly inhibited cell growth and arrested osteosarcoma cells in G0/G1 phase by influencing basic cell activities. Mistletoe extracellular vesicles offered val-miR218 adequate protection and facilitated the uptake of val-miR281 by human cells. Moreover, val-miR218 showed significant anti-tumor effects .

CONCLUSION

This study demonstrated the significant potential of val-miR218 regarding proliferation inhibition in various tumor cell lines and for osteosarcoma . Due to the increasing problems during chemotherapy, new therapeutic approaches are becoming more critical. The significant anti-cancer effects of medicinal plants derived miRNAs indicate a promising therapeutic strategy for treating cancer.

摘要

目的

近年来，人们对植物源微小RNA（miRNA）的治疗潜力越来越感兴趣，它们被认为是药用植物中的新型生物活性成分。欧洲中部常用作癌症辅助治疗的槲寄生（Viscum album L.）含有大量与人类疾病如癌症、心血管疾病和神经疾病相关的miRNA。本研究旨在调查槲寄生miRNA，特别是val-miR218，是否对骨肉瘤具有抗癌活性。

方法

评估了来自槲寄生的miRNA的抗癌作用。通过RNA测序确定val-miR218的靶标。通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹分析确认靶标的mRNA和蛋白质表达。通过双荧光素酶测定验证val-miR218与miRNA识别元件（MRE）之间的相互作用。研究了val-miR218对骨肉瘤的抑制作用。

结果

在槲寄生中这些丰富的miRNA中，val-miR218对骨肉瘤显示出很高的潜在抗癌作用。为了阐明其作用的分子机制，我们对与val-miR218相关的RNA及其下调的RNA进行了测序。结果，61个基因被认为是val-miR218的直接靶标。有趣的是，这些靶标与细胞周期、DNA复制和细胞形态等基本细胞功能相关，表明val-miR218通过影响基本细胞活动显著抑制细胞生长并使骨肉瘤细胞停滞在G0/G1期。槲寄生细胞外囊泡为val-miR218提供了充分的保护，并促进了人类细胞对val-miR218的摄取。此外，val-miR218显示出显著的抗肿瘤作用。