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首页> 外文期刊>EBioMedicine >Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway
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Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway

机译：Cinobufotalin通过刺激MAP2K4拮抗非肌肉肌球蛋白重链IIA /糖原合酶3β/β-catenin信号通路，强烈逆转EBV-miR-BART22诱导的顺铂耐药性

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Background Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related tumor. The role of EBV-encoding miR-BART22 is still unclear in NPC. This study aimed to identify the detailed mechanisms by which EBV-miR-BART22 functions as a tumor-promoting factor and evaluate the action of cinobufotalin in treating EBV-miR-BART22-overexpressing NPC cells. Methods Using real-time PCR, western blotting, immunohistochemistry, and In situ hybridization, we detected the expression of miR-BART22 and MAP2K4 in tissues and cells, as well as evaluated their clinical relevance in NPC patients. The effects of miR-BART22 on cell metastasis, stemness and DDP chemoresistance were examined by sphere formation assay, side population analysis, transwell, boyden, in vivo xenograft tumor mouse model et al. Western blotting, immunofluorescence staining, luciferase reporter assay, ChIP, EMSA and Co-IP assay et al. were performed to explore the detailed molecular mechanism of EBV-miR-BART22 in NPC. Finally, we estimated the effects and molecular basis of Cinobufotalin on EBV-miR-BART22-overexpressing NPC cells in vitro and in vivo assays. Findings We observed that EBV-miR-BART22 not only promoted tumor stemness and metastasis, but also enhanced the resistance to Cisplatin (DDP) in vitro and in vivo. Mechanistic analysis indicated that EBV-miR-BART22 directly targeted the MAP2K4 and upregulated non-muscle myosin heavy chain IIA ( MYH9 ) expression by PI3K/AKT/c-Jun -induced transcription. Further, MYH9 interacted with glycogen synthase 3β( GSK3β ) protein and induced its ubiquitin degradation by activating PI3K/AKT/c-Jun -induced ubiquitin transcription and the latter combined with increased TRAF6 E3 ligase, which further bound to GSK3β protein. Reductions in the GSK3β protein thus promoted β-catenin expression and nuclear translocation, which induced tumor stemness and the epithelial-to-mesenchymal transition (EMT) signals. Furthermore, we observed that cinobufotalin, a new chemically synthesized compound, significantly suppressed EBV-miR-BART22-induced DDP chemoresistance by upregulating MAP2K4 to suppress MYH9 / GSK3β/β-catenin and its downstream tumor stemness and EMT signals in NPC. Finally, clinical data revealed that increased miR-BART22 and reduced MAP2K4 expression caused the poor prognoses of NPC patients. Interpretation Our study provides a novel mechanism that cinobufotalin reversed the DDP chemoresistance and EMT induced by EBV-miR-BART22 in NPC.
机译：背景鼻咽癌（NPC）是一种与爱泼斯坦-巴尔病毒（EBV）相关的肿瘤。在NPC中，尚不清楚EBV编码miR-BART22的作用。这项研究旨在确定EBV-miR-BART22充当肿瘤促进因子的详细机制，并评估cinobufotalin在治疗EBV-miR-BART22过表达的NPC细胞中的作用。方法采用实时荧光定量PCR，Western blotting，免疫组织化学和原位杂交技术，检测miR-BART22和MAP2K4在组织和细胞中的表达，并评价其在NPC患者中的临床意义。通过球体形成测定，侧群分析，transwell，boyden，体内异种移植肿瘤小鼠模型等检查miR-BART22对细胞转移，干性和DDP化学抗性的影响。 Western印迹，免疫荧光染色，萤光素酶报告基因检测，ChIP，EMSA和Co-IP检测等。进行了探索NPC中EBV-miR-BART22的详细分子机制。最后，我们在体外和体内试验中评估了西诺布他林对EBV-miR-BART22过表达的NPC细胞的作用和分子基础。研究结果我们观察到EBV-miR-BART22不仅促进了肿瘤的干性和转移，而且在体外和体内都增强了对顺铂（DDP）的耐药性。机理分析表明，EBV-miR-BART22直接靶向MAP2K4，并通过PI3K / AKT / c-Jun诱导的转录上调了非肌球蛋白重链IIA（MYH9）的表达。此外，MYH9与糖原合酶3β（GSK3β）蛋白相互作用，并通过激活PI3K / AKT / c-Jun诱导的泛素转录来诱导其泛素降解，后者与增加的TRAF6 E3连接酶结合，后者进一步与GSK3β蛋白结合。因此，GSK3β蛋白的减少促进了β-catenin的表达和核易位，从而诱导了肿瘤干和上皮-间质转化（EMT）信号。此外，我们观察到一种新的化学合成化合物cinobufotalin通过上调MAP2K4抑制MYH9 /GSK3β/β-catenin及其下游肿瘤干和NPC中的EMT信号，显着抑制了EBV-miR-BART22诱导的DDP化学耐药性。最后，临床数据显示，miR-BART22的增加和MAP2K4表达的降低导致NPC患者的预后不良。解释我们的研究提供了一种新的机制，cinobufotalin逆转了EBV-miR-BART22在NPC中诱导的DDP化学耐药性和EMT。

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