BACKGROUND Malignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs. METHODS Potentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology. RESULTS The expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting β-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or β-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells. CONCLUSION miR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

中文翻译：

---

过表达miR-34c的外来体抑制恶性行为并逆转鼻咽癌的放射抵抗力。

背景技术恶性行为和放射抵抗严重限制了放射治疗（RT）在鼻咽癌（NPC）中的疗效，与肿瘤进展和不良预后有关。间充质干细胞（MSCs）被用作多种肿瘤的治疗工具。这项研究的目的是揭示肿瘤抑制基因microRNA-34c-5p（miR-34c）对NPC发育和放射抵抗的作用，并证实源自MSCs的过表达miR-34c的外泌体恢复了对NPC放射治疗的敏感性。 。方法通过细胞测序，Gene Expression Omnibus（GEO）数据库分析和70例患者的临床血清样本分析，筛选潜在活性的microRNA。通过蛋白质印迹，定量逆转录PCR（qRT-PCR）检测基因和蛋白质的表达，和免疫组化（IHC）。检测了NPC的增殖，凋亡，侵袭，迁移和放射抗性。荧光素酶报告基因测定用于验证微RNA与其下游靶标的相互作用。MSCs外泌体通过超滤分离并通过电子显微镜和纳米粒子跟踪技术验证。结果miR-34c的表达与鼻咽癌的发生和耐药有关。体外和体内实验表明，miR-34c的过表达通过靶向β-Catenin抑制NPC中的恶性行为，例如侵袭，迁移，增殖和上皮-间质转化（EMT）。此外，我们发现在NPC中，miR-34c过表达或β-catenin敲低减轻了放射抵抗。来自miR-34c转染的MSC的外泌体减弱了NPC的侵袭，迁移，扩散和EMT。此外，miR-34c过表达的外泌体极大地增加了辐射诱导的NPC细胞凋亡。结论miR-34c是NPC中的抑癌药miR，可抑制恶性行为以及肿瘤的放射抵抗性。因此，通过MSC外泌体将miR-34c外源递送至NPC可抑制肿瘤进展并提高RT的效率。IR与miR-34c过表达的外泌体联合使用可能是治疗放射性NPC的有效方法。通过MSC外泌体将miR-34c外源递送至NPC可抑制肿瘤进展并提高RT的效率。IR与miR-34c过表达的外泌体联合使用可能是治疗放射性NPC的有效方法。通过MSC外泌体将miR-34c外源递送至NPC可抑制肿瘤进展并提高RT的效率。IR与miR-34c过表达的外泌体联合使用可能是治疗放射性NPC的有效方法。