Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion.
Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion.
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长非编码 RNA RP11-115N4.1 通过与 HNRNPH3 相互作用并增强不明原因复发性流产中 HSP70 的转录来促进炎症反应
DOI：
10.3389/fimmu.2021.717785
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发表时间：
2021
影响因子：
7.3
通讯作者：
Chen H
中科院分区：
文献类型：
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作者：
Liu M;Sun X;Zhu L;Zhu M;Deng K;Nie X;Mo H;Du T;Huang B;Hu L;Liang L;Wang D;Luo Y;Yi J;Zhang J;Zhong X;Cao C;Chen H
背景不明原因复发性自然流产（URSA）是一种常见的妊娠并发症，病因不明。ursa相关的lncrna有望成为潜在的诊断生物标志物，并可能与疾病发病机制有关。目的研究非妊娠URSA患者与匹配的健康对照女性外周血中lncrna的差异，探讨差异lncrna导致URSA的可能机制。方法利用lncRNA芯片分析5例未妊娠URSA患者和5例健康对照患者外周血中lncRNA的表达。在体外进一步研究ursa相关lncrna的功能。结果在非妊娠URSA患者外周血中，RP11-115N4.1是差异表达最多的lncRNA，高度上调（P = 3.63E-07, Fold change = 2.96），并且在约26.67%的额外患者中进一步验证了这种失调（4/15）。人外周血淋巴细胞和单核细胞均检测到RP11-115N4.1的表达，体外过表达RP11-115N4.1可显著降低K562细胞的增殖能力。此外，通过转录组分析发现，热休克HSP70基因（HSPA1A和HSPA1B）在RP11-115N4.1过表达时显著上调(HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B （P = 2.26E-06, Fold change = 2.99）。RNA拉下和RNA免疫沉淀（RIP）分析表明，RP11-115N4.1直接结合HNRNPH3蛋白，进而激活热休克蛋白（HSP70），通过蛋白相互作用和HNRNPH3敲低实验分析。最重要的是，在URSA患者的血清和RP11-115N4.1活化的K562细胞的上清液中也证实了HSP70的高表达，上清液中的HSP70可以通过诱导IL-6、IL-1β和TNF-α加重单核细胞的炎症反应，抑制滋养细胞的迁移，这可能与URSA有关。结论激活RP11-115N4.1可通过与HNRNPH3结合，显著提高HSP70蛋白水平，从而调节免疫应答，与URSA相关。此外，RP11-115N4.1可能是URSA新的病因学生物标志物和新的治疗靶点。
Background Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis. Objective To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA. Methods We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro. Results RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1β, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA. Conclusion Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.
LIT 和 MLR-Bf 对既往早期复发性流产妇女免疫生物标志物和妊娠结局的影响：一项回顾性研究
影响因子：
7.3
作者：
Meng L;Tan J;Du T;Lin X;Zhang S;Nie X;Xie H;Lin J;Zhang J;Hui C
通讯作者：
Hui C