Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24.

IF 5.4 2区医学 Q1 CELL & TISSUE ENGINEERING Stem Cells Translational Medicine Pub Date : 2024-11-18 DOI:10.1093/stcltm/szae087

Weizhao Li, Chi Zhang, Tianshun Gao, Yazhou Sun, Huan Yang, Lixiang Liu, Ming Shi, Lu Ding, Changlin Zhang, David Y B Deng, Tian Li

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Abstract

Background: Cervical cancer is often caused by persistent high-risk human papillomavirus (HPV) infection, causing precancerous lesions. Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEV) exhibit diverse effects on tumors. This study investigates hucMSC-sEV, the impact and mechanisms on HPV-positive cervical precancerous lesion cells to provide new treatment insights.

Materials and methods: We previously obtained hucMSC and hucMSC-sEV. In vitro experiments evaluated hucMSC-sEV effects on the proliferation and migration of S12 cells (derived from cervical precancerous lesions). Bioinformatics identified key microRNA components, and their impact on S12 cell proliferation and migration was investigated. The target gene of the microRNA component was predicted and confirmed via bioinformatics and dual-luciferase reporter assays. Lentiviral systems overexpressed target gene in S12 cells to examine the effects on microRNA impacts. SH-42 inhibitor was used to investigate target gene treatment potential. Immunohistochemistry assessed target gene expression in cervical precancerous lesions tissue.

Results: hucMSC-sEV significantly inhibited S12 cell proliferation and migration. Bioinformatics identified miR-370-3p as an effective cargo, which also suppressed S12 cell proliferation and migration. miR-370-3p was confirmed targeting DHCR24 (24-Dehydrocholesterol Reductase). DHCR24 overexpression reversed miR-370-3p's inhibitory effects, while SH-42 counteracted DHCR24 overexpression's promoting effects. Clinical specimen analysis supported these findings, demonstrating a positive correlation between DHCR24 protein expression and cervical precancerous lesions' progression.

Conclusions: hucMSC-sEV inhibits S12 cell proliferation and migration, mediated by miR-370-3p targeting DHCR24 to regulate cellular cholesterol content. DHCR24 inhibition reduces the cholesterol level and cell functions, suggesting its potential as a therapeutic target in cervical precancerous lesions.

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人脐带间充质干细胞小细胞外囊泡衍生的 miR-370-3p 通过靶向 DHCR24 抑制宫颈癌前病变。

背景：宫颈癌通常是由持续的高危人乳头瘤病毒（HPV）感染引起的癌前病变。人脐带间充质干细胞衍生的细胞外小泡（hucMSC-sEV）对肿瘤有多种影响。本研究探讨了hucMSC-sEV、其对HPV阳性宫颈癌前病变细胞的影响和机制，以提供新的治疗见解：我们之前获得了hucMSC和hucMSC-sEV。体外实验评估了 hucMSC-sEV 对 S12 细胞（来源于宫颈癌前病变）增殖和迁移的影响。生物信息学确定了关键的微RNA成分，并研究了它们对S12细胞增殖和迁移的影响。通过生物信息学和双荧光素酶报告实验预测并确认了微RNA成分的靶基因。慢病毒系统在 S12 细胞中过表达靶基因，以研究其对 microRNA 的影响。SH-42抑制剂用于研究靶基因的治疗潜力。免疫组化评估了宫颈癌前病变组织中靶基因的表达。生物信息学发现 miR-370-3p 也是抑制 S12 细胞增殖和迁移的有效载体。DHCR24 的过表达逆转了 miR-370-3p 的抑制作用，而 SH-42 则抵消了 DHCR24 过表达的促进作用。结论：hucMSC-sEV能抑制S12细胞的增殖和迁移，其作用机制是通过miR-370-3p靶向DHCR24来调节细胞中胆固醇的含量。抑制 DHCR24 可降低胆固醇水平和细胞功能，这表明它有可能成为宫颈癌前病变的治疗靶点。

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来源期刊

Stem Cells Translational Medicine CELL & TISSUE ENGINEERING-

CiteScore

12.90

自引率

3.30%

发文量

140

审稿时长

6-12 weeks

期刊介绍： STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal. STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes. The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.