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首页> 外文期刊>Journal of experimental & clinical cancer research : >Radiation induces NORAD expression to promote ESCC radiotherapy resistance via EEPD1/ATR/Chk1 signalling and by inhibiting pri-miR-199a1 processing and the exosomal transfer of miR-199a-5p
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Radiation induces NORAD expression to promote ESCC radiotherapy resistance via EEPD1/ATR/Chk1 signalling and by inhibiting pri-miR-199a1 processing and the exosomal transfer of miR-199a-5p

机译：辐射诱导诺拉德的表达通过EEPD1 / ATR / CHK1信号传导促进ESCC放射疗法抗性，并通过抑制Pri-miR-19a1加工和MiR-199A-5P的外泌体转移

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Radioresistance, a poorly understood phenomenon, results in the failure of radiotherapy and subsequent local recurrence, threatening a large proportion of patients with ESCC. To date, lncRNAs have been reported to be involved in diverse biological processes, including radioresistance. FISH and qRT–PCR were adopted to examine the expression and localization of lncRNA-NORAD, pri-miR-199a1 and miR-199a-5p. Electron microscopy and nanoparticle tracking analysis (NTA) were conducted to observe and identify exosomes. High-throughput microRNAs sequencing and TMT mass spectrometry were performed to identify the functional miRNA and proteins. A series of in vitro and in vivo experiments were performed to investigate the biological effect of NORAD. ChIP, RIP-qPCR, co-IP and dual-luciferase reporter assays were conducted to explore the interaction of related RNAs and proteins. We show here that DNA damage activates the noncoding RNA NORAD, which is critical for ESCC radioresistance. NORAD was expressed at high levels in radioresistant ESCC cells. Radiation treatment promotes NORAD expression by enhancing H3K4me2 enrichment in its sequence. NORAD knockdown cells exhibit significant hypersensitivity to radiation in vivo and in vitro. NORAD is required to initiate the repair and restart of stalled forks, G2 cycle arrest and homologous recombination repair upon radiation treatment. Mechanistically, NORAD inhibits miR-199a-5p expression by competitively binding PUM1 from pri-miR-199a1, inhibiting the processing of pri-miR-199a1. Mature miR-199a-5p in NORAD knockdown cells is packaged into exosomes; miR-199a-5p restores the radiosensitivity of radioresistant cells by targeting EEPD1 and then inhibiting the ATR/Chk1 signalling pathway. Simultaneously, NORAD knockdown inhibits?the ubiquitination of PD-L1, leading to a better response to radiation and anti-PD-1 treatment in a mouse model. Based on the findings of this study, lncRNA-NORAD represents a potential treatment target for improving the efficiency of immunotherapy in combination with radiation in ESCC.
机译：辐射探测器，理解的现象不良，导致放疗失败和随后的局部复发，威胁大部分ESCC患者。迄今为止，据报道，LNCRNA涉及不同的生物过程，包括辐射耐心。采用鱼类和QRT-PCR检查LNCRNA-NORAD，PRI-MIR-199A1和MIR-199A-5P的表达和定位。进行电子显微镜和纳米粒子跟踪分析（NTA）以观察和鉴定外泌体。进行高通量MicroRNAS测序和TMT质谱以鉴定功能性miRNA和蛋白质。进行了一系列体外和体内实验，以研究挪亚的生物学效果。进行CHIP，RIP-QPCR，CO-IP和双荧光素酶报告结果以探讨相关RNA和蛋白质的相互作用。我们在这里展示DNA损伤激活非分量RNA Norad，这对于ESCC辐射避险率至关重要。挪亚在辐射患者ESCC细胞中以高水平表达。通过在其序列中提高H3K4ME2富集来促进诺拉的表达。诺拉德敲低细胞对体内和体外的辐射表现出显着的超敏反应。挪亚必须在放射治疗时启动停滞的叉，G2周期停滞和同源重组修复。机械地，挪亚通过竞争性地结合PRI-MIR-199A1来抑制MIR-199A-5P表达，抑制PRI-MIR-199A1的处理。 Norad敲低细胞中的成熟MiR-199A-5P包装成外泌体; MiR-199A-5P通过靶向EEPD1来恢复放射性细胞的放射敏感性，然后抑制ATR / CHK1信号通路。同时，诺拉德敲低抑制？PD-L1的泛素化，导致对小鼠模型中的辐射和抗PD-1治疗更好地反应。基于本研究的发现，LNCRNA-NORAD代表了提高免疫疗法效率与ESCC辐射的潜在治疗靶标。

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