NPL4靶向抑制剂双硫仑对T细胞肿瘤泛素-蛋白酶体通路相关基因表达的影响

蔡清华; 王彩霞; 陈存特

doi:10.12019/j.issn.1671-5144.202404028

NPL4靶向抑制剂双硫仑对T细胞肿瘤泛素-蛋白酶体通路相关基因表达的影响

The Effect of NPL4-Targeted Inhibitor Disulfiram on the Expression of Genes Related to the Ubiquitin-Proteasome Pathway in T-Cell Malignancies

摘要

摘要:
目的我们前期的研究表明，双硫仑（disulfiram，DSF）通过核蛋白定位蛋白4同源物（nuclear protein localization protein 4 homolog，NPL4）介导的泛素-蛋白酶体通路发挥抗T细胞肿瘤主要包括急性T淋巴白血病（T-cell acute lymphoblastic leukemia，T-ALL）和T细胞淋巴瘤（T-cell lymphoma，TCL）的作用。本研究旨在探讨双硫仑对T细胞肿瘤中泛素-蛋白酶体通路相关基因表达的调节作用，为T细胞肿瘤的精准靶向治疗提供依据。
方法应用0.4 μM双硫仑处理T-ALL细胞株Jurkat 48 h，采用转录组测序分析显著性差异表达的基因，并采用10例T细胞肿瘤样本（GZFPH数据集）进行实时荧光定量PCR验证差异基因相对表达水平。最后，从TARGET和GSE58445数据库中下载262例T-ALL和140例TCL的转录组测序数据进行生存分析。
结果 0.4 μM 双硫仑处理 Jurkat细胞48 h后，在泛素-蛋白酶体通路中，有86个下调和35个上调的基因；其中，单因素Cox回归和生存曲线分析发现，仅有泛素结合酶E2 J1（ubiquitin conjugating enzyme E2 J1，UBE2J1）基因的低表达与TARGET和GSE58445数据集中T-ALL和TCL患者的不良预后相关（P<0.05）。将UBE2J1的表达水平、年龄和性别纳入单因素和多因素Cox回归分析，结果提示UBE2J1的低表达是T-ALL和TCL患者的独立预后影响因子（P<0.05）。
结论双硫仑可调控UBE2J1基因的表达，其低表达与T细胞肿瘤患者的不良预后相关，为进一步阐明双硫仑的抗肿瘤作用及其调控的UBE2J1基因作为T细胞肿瘤的危险分层的分子标志物提供理论依据。

Abstract:
Objective Our previous studies have demonstrated that disulfiram (DSF) exerts antitumor effects on T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), through the ubiquitin-proteasome pathway mediated by nuclear protein localization protein 4 homolog (NPL4). This study aims to investigate the regulatory effects of disulfiram on the expression of genes related to the ubiquitin-proteasome pathway in T-cell malignancies, providing a basis for precision targeted therapy of T-cell malignancies.
Methods Jurkat cells, a T-ALL cell line, were treated with 0.4 μM disulfiram for 48 hours. Transcriptome sequencing was performed to analyze differentially expressed genes, and real-time quantitative PCR was used to validate the relative expression levels of these genes in 10 T-cell malignancy samples (GZFPH dataset). Additionally, transcriptome sequencing data from 262 cases of T-ALL and 140 cases of TCL were downloaded from the TARGET and GSE58445 databases for survival analysis.
Results After treating Jurkat cells with 0.4 μM disulfiram for 48 hours, 86 genes were downregulated and 35 genes were upregulated in the ubiquitin-proteasome pathway. Among these genes, univariate Cox regression and survival curve analysis revealed that only low expression of ubiquitin-conjugating enzyme E2 J1 (UBE2J1) was associated with poor prognosis in patients with T-ALL and TCL in both the TARGET and GSE58445 datasets (P < 0.05). When incorporating UBE2J1 expression level, age, and gender into univariate and multivariate Cox regression analyses, low expression of UBE2J1 emerged as an independent prognostic factor for patients with T-ALL and TCL (P < 0.05).
Conclusions Disulfiram can regulate the expression of the UBE2J1 gene, and its low expression is associated with poor prognosis in patients with T-cell malignancies. This study provides a theoretical basis for further elucidating the antitumor effects of disulfiram and the potential use of UBE2J1 as a biomarker for risk stratification in T-cell malignancies.

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