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Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion
Molecular Human Reproduction ( IF 4 ) Pub Date : 2021-07-02 , DOI: 10.1093/molehr/gaab044
Xiao-Xiao Zhu 1, 2, 3 , Xun-Qiang Yin 4, 5, 6 , Guo-Zhen Hei 7 , Ran Wei 1 , Qiang Guo 1 , Lin Zhao 1 , Zhen Zhang 1 , Chu Chu 1, 3 , Xiao-Xiao Fu 1, 3 , Ke Xu 1, 3 , Xia Li 1, 2, 3
Affiliation  

Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Dendritic cells (DCs) are thought to confer fetal–maternal immunotolerance and play a crucial role in ensuring a successful pregnancy. A decrease of plasmacytoid dendritic cells (pDCs) was found to be involved in RSA, but the underlying mechanisms of decreased pDC in RSA remain unclear. MicroRNAs (miRNAs) play critical roles in RSA as well as the development, differentiation and functional regulation of pDCs; however, the regulatory effect of miRNAs on pDC in RSA has not been fully investigated. Here we demonstrated that both the proportion of pDC and signal transducer and activator of transcription (STAT3)/transcription factor 4 (Tcf4/E2-2) expression decreased in the peripheral blood mononuclear cells and decidua of patients with RSA compared to those with normal pregnancy (NP), and there was a significantly positive correlation between pDC and STAT3 mRNA. MiRNA microarray assay and quantitative reverse transcription PCR results showed that miR-6875-5p expression was markedly increased in women with RSA and negatively correlated with mRNA expression level of STAT3. Up-regulated miR-6875-5p could sensitively discriminate patients with RSA from NP subjects. Overexpression of miR-6875-5p significantly down-regulated the mRNA expression of STAT3 and E2-2 as well as the protein and phosphorylation level of STAT3, while miR-6875-5p knockdown showed opposite results. Dual luciferase reporter verified that miR-6875-5p regulated STAT3 expression by directly binding to its 3'untranslated region. Overall, our results suggested that increased miR-6875-5p is involved in RSA by decreasing the differentiation of pDCs via inhibition of the STAT3/E2-2 signaling pathway. miR-6875-5p may be explored as a promising diagnostic marker and therapeutic target for RSA.

中文翻译:

增加的 miR-6875-5p 通过 STAT3/E2-2 通路抑制复发性自然流产中的浆细胞样树突状细胞分化

复发性自然流产(RSA)是早期妊娠的常见并发症。树突状细胞 (DC) 被认为赋予胎儿-母体免疫耐受性,并在确保成功怀孕方面发挥关键作用。发现浆细胞样树突状细胞 (pDC) 的减少与 RSA 相关,但 RSA 中 pDC 减少的潜在机制仍不清楚。MicroRNAs (miRNAs) 在 RSA 以及 pDCs 的发育、分化和功能调节中发挥关键作用;然而,miRNA对RSA中pDC的调节作用尚未得到充分研究。在这里,我们证明了与正常妊娠相比,RSA 患者外周血单个核细胞和蜕膜中 pDC 和信号转导和转录激活因子 (STAT3)/转录因子 4 (Tcf4/E2-2) 表达的比例均降低(NP), pDC 与 STAT3 mRNA 呈显着正相关。miRNA微阵列检测和定量逆转录PCR结果显示,在患有RSA的女性中,miR-6875-5p的表达显着增加,并且与STAT3的mRNA表达水平呈负相关。上调的 miR-6875-5p 可以敏感地区分 RSA 患者和 NP 受试者。过表达 miR-6875-5p 显着下调 STAT3 和 E2-2 的 mRNA 表达以及 STAT3 的蛋白和磷酸化水平,而 miR-6875-5p 敲低显示相反的结果。双荧光素酶报告基因证实 miR-6875-5p 通过直接结合其 3' 非翻译区来调节 STAT3 表达。总体而言,我们的结果表明增加的 miR-6875-5p 通过抑制 STAT3/E2-2 信号通路降低 pDC 的分化参与 RSA。可以探索 miR-6875-5p 作为 RSA 的有希望的诊断标志物和治疗靶点。
更新日期:2021-07-02
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