The oncogenic role of TRIP13 in clear cell renal cell carcinoma and the synergistic inhibitory effect of combined DCZ0415 and TI17 therapy

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-09-11 DOI:10.1016/j.genrep.2025.102336

Sen Wang , Boyu Zhang , Mengwei Song , Ying Zhou, Kadirya Asan, Zihao Yang, Jian Wang, Haiyan Lin, Xiaoxue Song, Xudong Yu, Jing Ji

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引用次数: 0

Abstract

This study integrated transcriptomic analysis with multidimensional bioinformatics approaches to systematically elucidate the regulatory roles of AAA+ ATPase family members in clear cell renal cell carcinoma (ccRCC). Through differential expression analysis of TCGA and GEO databases and construction of weighted gene co-expression networks (WGCNA), the key gene TRIP13 was identified. Experimental validation revealed that TRIP13 is significantly upregulated in ccRCC tissues and closely associated with poor patient prognosis, with high expression correlating with markedly reduced overall survival and progression-free survival. Molecular mechanism studies demonstrated that TRIP13 promotes tumor proliferation and migration by activating cell cycle-related pathways (e.g., G2/M checkpoint, E2F targets, normalized enrichment score > 3.0, p < 0.01). Single-cell RNA sequencing further revealed its specific enrichment during the S/G2M phase and regulation of proliferation marker genes such as PCNA. Inhibitor interaction analysis confirmed that DCZ0415 and TI17 synergistically suppress TRIP13 function by targeting critical residues like SER-187. Additionally, TRIP13 expression was positively correlated with the infiltration of effector memory T cells in the tumor microenvironment, suggesting its potential role in immunoregulation. This study identifies TRIP13 as a novel therapeutic target and prognostic biomarker for ccRCC, offering insights into targeted therapy and personalized treatment strategies.

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TRIP13在透明细胞肾细胞癌中的致瘤作用及DCZ0415与TI17联合治疗的协同抑制作用

本研究将转录组学分析与多维生物信息学方法相结合，系统地阐明了AAA+ atp酶家族成员在透明细胞肾细胞癌（ccRCC）中的调节作用。通过TCGA和GEO数据库的差异表达分析和加权基因共表达网络（WGCNA）的构建，确定了关键基因TRIP13。实验验证显示，TRIP13在ccRCC组织中显著上调，与患者预后不良密切相关，高表达与总生存期和无进展生存期显著降低相关。分子机制研究表明，TRIP13通过激活细胞周期相关通路（如G2/M检查点、E2F靶点、标准化富集评分>； 3.0, p < 0.01）促进肿瘤增殖和迁移。单细胞RNA测序进一步揭示了其在S/G2M期的特异性富集以及对增殖标记基因如PCNA的调控作用。抑制剂相互作用分析证实DCZ0415和TI17通过靶向SER-187等关键残基协同抑制TRIP13功能。此外，TRIP13的表达与肿瘤微环境中效应记忆T细胞的浸润呈正相关，提示其在免疫调节中的潜在作用。本研究确定了TRIP13作为ccRCC的新型治疗靶点和预后生物标志物，为靶向治疗和个性化治疗策略提供了见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.