E2F1 promotes LIHC malignant phenotype via NEK2-mediated Wnt/β-catenin and Notch activation and EMT

IF 1.9 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2026-01-01 Epub Date: 2026-04-02 DOI:10.1016/j.mrfmmm.2026.111935

Lingju Hong, Shaoying Ke, Shaoze Lin, Gongle Wu, Congren Wang

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Abstract

Background

Hepatocellular carcinoma (LIHC) is the most common primary liver cancer, with high recurrence and metastasis rates, and its molecular mechanisms remain incompletely understood.

Methods

The cancer genome atlas (TCGA) database was used to obtain LIHC-related information. TNMplot, gene expression profiling interactive analysis (GEPIA), and kaplan-meier plotter were used for differential gene expression analysis, visualization, and assessing the relationship between genes and patient survival. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were used to detect gene and protein expression levels. Cell transfection was used for gene knockdown and overexpression. Transwell and wound healing assays were used to evaluate cell migration and invasion. The jaspar database was used to predict transcription factor-gene interactions. Chromatin immunoprecipitation (ChIP) and dual-luciferase assays were used to validate transcription factor-gene binding.

Results

Never in mitosis gene a related kinase 2 (NEK2) was highly expressed in LIHC, and its high expression potentially had a negative impact on patient survival. NEK2 knockdown reduced the migration and invasion abilities of LIHC cells, decreased the expression of epithelial-mesenchymal transition (EMT) markers neural cadherin (N-cadherin) and vimentin, and increased epithelial cadherin (E-cadherin) expression, whereas NEK2 overexpression showed the opposite effects. E2F transcription factor 1 (E2F1) was also highly expressed in LIHC and positively regulated NEK2, exhibiting similar regulatory effects on LIHC cells. Moreover, NEK2 was positively correlated with Wnt/β-catenin marker catenin beta 1 (CTNNB1), as well as Notch signaling markers notch receptor 1 (NOTCH1), jagged canonical notch ligand 1 (JAG1), HES family BHLH transcription factor 1 (HES1), and HES-related family BHLH transcription factor with YRPW motif 1 (HEY1).

Conclusion

The E2F1/NEK2 axis promotes the activation of Wnt/β-catenin and Notch signaling pathways and induces EMT to drive malignant behavior of LIHC cells.

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E2F1通过nek2介导的Wnt/β-catenin、Notch激活和EMT促进LIHC恶性表型

肝细胞癌（hepatocellular carcinoma， LIHC）是最常见的原发性肝癌，具有高复发和转移率，其分子机制尚不完全清楚。方法利用肿瘤基因组图谱（TCGA）数据库获取lihc相关信息。使用TNMplot、基因表达谱交互分析（GEPIA）和kaplan-meier绘图仪进行差异基因表达分析、可视化和评估基因与患者生存之间的关系。采用逆转录定量聚合酶链反应（RT-qPCR）和western blot （WB）检测基因和蛋白的表达水平。细胞转染法进行基因敲除和过表达。Transwell和伤口愈合试验用于评估细胞迁移和侵袭。jaspar数据库用于预测转录因子-基因相互作用。使用染色质免疫沉淀（ChIP）和双荧光素酶测定来验证转录因子与基因的结合。结果有丝分裂基因相关激酶2 （NEK2）在LIHC中高表达，其高表达可能对患者的生存产生负面影响。NEK2的下调降低了LIHC细胞的迁移和侵袭能力，降低了上皮-间质转化（EMT）标志物神经钙粘蛋白（N-cadherin）和vimentin的表达，增加了上皮钙粘蛋白（E-cadherin）的表达，而NEK2的过表达则表现出相反的作用。E2F转录因子1 （E2F1）在LIHC中也高表达，并正向调节NEK2，对LIHC细胞具有类似的调节作用。此外，NEK2与Wnt/β-连环蛋白标记物catenin β 1 （CTNNB1）、Notch信号标记物Notch受体1 （NOTCH1）、锯齿状典型缺口配体1 （JAG1）、HES家族BHLH转录因子1 （HES1）、HES相关家族BHLH转录因子YRPW motif 1 （HEY1）呈正相关。结论E2F1/NEK2轴促进Wnt/β-catenin和Notch信号通路的激活，诱导EMT驱动LIHC细胞的恶性行为。

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

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.