Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China.
Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Antiviral Res. 2023 May;213:105584. doi: 10.1016/j.antiviral.2023.105584. Epub 2023 Apr 4.
Chronic hepatitis B (CHB) patients treated with interferon shows encouraging results. However, its clinical efficacy is limited by significant individual differences in treatment responses. We identified an interferon-inducible effector, TRIM22, as the likely causal target of such differential responses. We found that TRIM22 was highly expressed in interferon-responsive patients and negatively correlated with HBV DNA and HBeAg serum levels. Stable cells overexpressing TRIM22 carried significantly less HBsAg, HBeAg, and HBV DNA, and cells with knocked-down TRIM22 by shRNA displayed higher levels of these markers than controls. Integrated bioinformatics analysis and subsequent experiments revealed that TRIM22 overexpression significantly increased the supernatant levels of IL-1β and IL-8, two important cytokines of NOD2/NF-κB pathway involved in interferon-induced antiviral activities. We identified three candidate microRNAs binding to 3'UTR of TRIM22 at various locations through typical imperfect paring using the TargetScan program. MiR-548c-3p appeared to be highly expressed, while the TRIM22 level was low in the suboptimal response group of CHB patients. The Luciferase reporter assay revealed an interaction between miR-548c-3p and the 3'UTR of TRIM22, leading to a controlled suppression of TRIM22 endogenous expression. This resulted in interferon's substantially weakened therapeutic efficacy, as indicated by the elevation of the serum levels of HBsAg, HBeAg and HBV DNA in miR-548c-3p-transfected HepAD38 cells. Our study demonstrated that a particular miR-548c-3p is the key negative regulator of TRIM22 in CHB patients with a weak response to interferon treatment, providing a novel marker and target in interferon-α therapy evaluation.
慢性乙型肝炎（CHB）患者接受干扰素治疗显示出令人鼓舞的效果。然而，其临床疗效受到治疗反应个体差异的显著限制。我们鉴定了干扰素诱导的效应因子 TRIM22，作为这种差异反应的可能因果靶标。我们发现，TRIM22 在干扰素反应性患者中高度表达，与 HBV DNA 和 HBeAg 血清水平呈负相关。过表达 TRIM22 的稳定细胞携带的 HBsAg、HBeAg 和 HBV DNA 显著减少，而通过 shRNA 敲低 TRIM22 的细胞显示出比对照更高的这些标志物水平。综合生物信息学分析和随后的实验表明，TRIM22 过表达显著增加了上清液中两种重要的 NOD2/NF-κB 途径细胞因子白细胞介素 1β（IL-1β）和白细胞介素 8（IL-8）的水平，这两种细胞因子参与干扰素诱导的抗病毒活性。我们使用 TargetScan 程序通过典型的不完全配对鉴定了三个候选 microRNA 结合到 TRIM22 的 3'UTR 的不同位置。miR-548c-3p 似乎高度表达，而在 CHB 患者的亚最佳反应组中 TRIM22 水平较低。荧光素酶报告基因检测显示 miR-548c-3p 与 TRIM22 的 3'UTR 之间存在相互作用，导致 TRIM22 内源性表达受到控制抑制。这导致干扰素的治疗效果显著减弱，如 miR-548c-3p 转染 HepAD38 细胞后 HBsAg、HBeAg 和 HBV DNA 血清水平的升高所表明的。我们的研究表明，在干扰素治疗反应较弱的 CHB 患者中，特定的 miR-548c-3p 是 TRIM22 的关键负调控因子，为干扰素-α治疗评估提供了新的标志物和靶标。
