Ma Shanshan, Xie Zhongyang, Zhang Lingjian, Yang Ya, Jiang He, Ouyang Xiaoxi, Zhao Yalei, Liu Qiuhong, Xu Xiaowei, Li Lanjuan
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Front Mol Biosci. 2021 Apr 28;8:657631. doi: 10.3389/fmolb.2021.657631. eCollection 2021.
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening disease with a high mortality rate; the systemic inflammatory response plays a vital role in disease progression. We aimed to determine if a miRNA-mRNA co-regulatory network exists in the peripheral blood mononuclear cells (PBMCs) of HBV-ACLF patients, which might be important for prognosis.
In patients with HBV-ACLF meeting COSSH-ACLF criteria, age, liver cirrhosis and INR were independent risk factors for 28-day and 90-day poor prognosis. COSSH-ACLFs was a superior prognostic model. mir-6840-3p-JADE2 may promote the progression of ACLF and lead to poor prognosis. Meanwhile, mir-6840-3p and mir-6861-3p can be used as markers of short-term poor prognosis. Finally, ALSS treatment is not only the blood material exchange of patients, but also changes part of the immune state of patients. Among them, cytokine cytokine receptor interaction may play an important role in determining the therapeutic effect.
Transcriptome-wide microRNA (miRNA) and mRNA microarrays were used to define the miRNA and mRNA expression profiles of the PBMCs of HBV-ACLF patients in a discovery cohort. The targets of the miRNAs were predicted. We built a miRNA-mRNA regulatory network through bioinformatics analysis, and used quantitative real-time polymerase chain reaction (qRT-PCR) to assess the importance of candidate miRNAs and mRNAs. We also assessed the direct and transcriptional regulatory effects of miRNAs on target mRNAs using a dual-luciferase reporter assay.
The miRNA/mRNA PBMC expression profiles of the discovery cohort, of whom eight survived and eight died, revealed a prognostic interactive network involving 38 miRNAs and 313 mRNAs; this was constructed by identifying the target genes of the miRNAs. We validated the expression data in another cohort, of whom 43 survived and 35 died; miR-6840-3p, miR-6861-3p, JADE2, and NR3C2 were of particular interest. The levels of miR-6840-3p and miR-6861-3p were significantly increased in the PBMCs of the patients who died, and thus predicted prognosis (areas under the curve values = 0.665 and 0.700, respectively). The dual-luciferase reporter assay indicated that miR-6840-3p directly targeted JADE2.
We identified a prognostic miRNA-mRNA co-regulatory network in the PBMCs of HBV-ACLF patients. miR-6840-3p-JADE2 is a potential miRNA-mRNA pair contributing to a poor prognosis.
乙型肝炎病毒相关慢加急性肝衰竭（HBV-ACLF）是一种威胁生命且死亡率高的疾病；全身炎症反应在疾病进展中起关键作用。我们旨在确定HBV-ACLF患者外周血单个核细胞（PBMC）中是否存在miRNA-mRNA共调控网络，这可能对预后很重要。
在符合COSSH-ACLF标准的HBV-ACLF患者中，年龄、肝硬化和国际标准化比值（INR）是28天和90天预后不良的独立危险因素。COSSH-ACLF是一个更好的预后模型。mir-6840-3p-JADE2可能促进ACLF进展并导致预后不良。同时，mir-6840-3p和mir-6861-3p可作为短期预后不良的标志物。最后，人工肝支持系统（ALSS）治疗不仅是患者的血液物质交换，还改变了患者部分免疫状态。其中，细胞因子-细胞因子受体相互作用可能在决定治疗效果中起重要作用。
在一个发现队列中，使用全转录组微小RNA（miRNA）和信使核糖核酸（mRNA）微阵列来确定HBV-ACLF患者PBMC的miRNA和mRNA表达谱。预测了miRNA的靶标。我们通过生物信息学分析构建了一个miRNA-mRNA调控网络，并使用定量实时聚合酶链反应（qRT-PCR）评估候选miRNA和mRNA的重要性。我们还使用双荧光素酶报告基因检测评估了miRNA对靶标mRNA的直接和转录调控作用。
发现队列中有8例存活和8例死亡患者的miRNA/mRNA PBMC表达谱揭示了一个涉及38个miRNA和313个mRNA的预后交互网络；这是通过鉴定miRNA的靶基因构建的。我们在另一个队列中验证了表达数据，该队列中有43例存活和35例死亡；其中miR-6840-3p、miR-6861-3p、JADE2和NR3C2特别受关注。死亡患者PBMC中miR-6840-3p和miR-6861-3p水平显著升高，因此可预测预后（曲线下面积值分别为0.665和0.700）。双荧光素酶报告基因检测表明miR-6840-3p直接靶向JADE2。
我们在HBV-ACLF患者的PBMC中鉴定出一个预后性miRNA-mRNA共调控网络。miR-6840-3p-JADE2是一对可能导致预后不良的潜在miRNA-mRNA组合。
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