Abstract
BackgroundCervical cancer is the most prevalent gynecological malignancies accompanied by high mortality, where finding a more effective therapeutic option for cervical cancer is necessary. The inhibitory role of microRNAs (miRNAs) derived from the extracellular vesicles (EVs) of the bone marrow mesenchymal stem cells (BMSCs) was analyzed in cervical cancer.MethodsExpression of miR-375 was examined by RT-qPCR in cervical cancer cell lines. The targeting relation between miR-375 and maternal embryonic leucine zipper kinase (MELK) was predicted by bioinformatics analysis and verified by dual-luciferase reporter gene assay. Isolated BMSCs were transfected with lentivirus-mediated vectors, followed by EV extraction. The morphology of EVs was then identified using a NanoSight particle size analyzer and transmission electron microscope (TEM). The biological properties of cervical cancer cells were evaluated using Transwell, EdU, and TUNEL assays, respectively. Xenograft tumors in nude mice were observed to assess cervical tumorigenesis in vivo.ResultsLow expression of miR-375 and high expression of MELK were detected in cervical cancer samples. MELK was identified as the target gene of miR-375, which was negatively correlated with miR-375 levels. Overexpression of miR-375 suppressed proliferation, migration, and invasion of cervical cancer cells, but enhanced cell apoptosis by cooperating with downregulated MELK expression. miR-375 transferred from BMSC-derived EVs exerted the same effects on cell biological activities. Xenograft assays in vivo proved that miR-375 from BMSC-derived EVs inhibited tumor growth.ConclusionThe present study highlighted the role of miR-375 from BMSC-derived EVs in suppressing the progression of cervical cancer, which may contribute to the discovery of novel potential biomarkers for cervical cancer therapy.
Highlights
Cervical cancer is the most prevalent gynecological malignancies accompanied by high mortality, where finding a more effective therapeutic option for cervical cancer is necessary
The results showed that compared to the normal cervical epithelial cell line HcerEpic, the expression of miR-375 was decreased and the expression of maternal embryonic leucine zipper kinase (MELK) was increased in the cervical cancer cell lines CaSki, C33A, HeLa, and SiHa (Fig. 1h)
The results revealed that the apoptosis of cells co-cultured with extracellular vesicles (EVs) isolated from miR-375-transfected bone marrow mesenchymal stem cells (BMSCs) was promoted, which demonstrated that miR-375 from BMSC-derived EVs could promote apoptosis in cervical cancer cells (Fig. 6c)
Summary
Cervical cancer is the most prevalent gynecological malignancies accompanied by high mortality, where finding a more effective therapeutic option for cervical cancer is necessary. The inhibitory role of microRNAs (miRNAs) derived from the extracellular vesicles (EVs) of the bone marrow mesenchymal stem cells (BMSCs) was analyzed in cervical cancer. Bone marrow mesenchymal stromal/stem cells (BMSCs) have been reported to exert therapeutic functions in various diseases due to their properties of differentiation and self-renewal [4]. The extracellular vesicles (EVs) released from the MSCs have been demonstrated to have great therapeutic potentials in a variety of human diseases via the delivery of RNA, proteins, or bioactive lipid cargos [5]. Recent research indicates an important role of microRNAs (miRNAs) released from BMSC-derived EVs in disease regulation [7, 8]. Little is known about the specific role of BMSC-derived EVs delivering miRNAs in the pathogenesis of cervical cancer. We aim to explore the potential regulatory mechanism of miRNA shuttled by BMSC-derived EVs in the pathogenesis of cervical cancer
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