The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2023-07-01 DOI:10.1016/j.mrfmmm.2023.111837

Lidan Zhang, Lei Shi

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Abstract

Background

Lung adenocarcinoma (LUAD) represents the predominant subtype of lung cancer. MELTF, an oncogene, exhibits high expression in various cancer tissues. Nevertheless, the precise role of MELTF in the progression of LUAD remains enigmatic. This work was devised to investigate the effect of MELTF on LUAD progression and its underlying mechanism.

Methods

mRNA expression data of LUAD were from The Cancer Genome Atlas database, and the enrichment pathway of MELTF was analyzed. The upstream transcription factors of MELTF were predicted, and the correlation between MELTF and E2F1 as well as the expression of the two in LUAD tissues were dissected by bioinformatics. The expression of MELTF and E2F1 in LUAD tissues and cells was assayed by qRT-PCR. Effects of MELTF/E2F1 on proliferation, migration, and invasion of LUAD cells were tested by CCK-8, colony formation, and Transwell assays. The binding relationship between E2F1 and MELTF was estimated by dual-luciferase reporter gene assay and ChIP assay. Western blot was utilized to assay the expression of Notch signaling pathway-related proteins in different treatment groups.

Results

Bioinformatics analysis and qRT-PCR results exhibited high expression of E2F1 and MELTF in LUAD tissues and cells, respectively. Dual-luciferase reporter gene assay and ChIP assay ascertained the binding of E2F1 to MELTF. MELTF was ascertained to enrich the Notch signaling pathway by bioinformatics means. In cell experiments, MELTF was shown to foster the malignant progression of LUAD cells and promoted the expression of NOTCH1 and HES1 proteins, but RO4929097 offset the effect of MELTF on cells. Rescue assay confirmed that E2F1 activated MELTF to promote LUAD progression via the Notch signaling pathway.

Conclusion

Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.

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E2F1/METF轴通过调节Notch信号通路促进肺腺癌的进展。

背景：肺腺癌（LUAD）是癌症的主要亚型。MELTF是一种癌基因，在各种癌症组织中都有高表达。然而，MELTF在LUAD进展中的确切作用仍然是个谜。这项工作旨在研究MELTF对LUAD进展的影响及其潜在机制。方法：从癌症基因组图谱数据库中获取LUAD的mRNA表达数据，分析MELTF的富集途径。对MELTF的上游转录因子进行了预测，并通过生物信息学分析了MELTF与E2F1的相关性以及两者在LUAD组织中的表达。通过qRT-PCR检测MELTF和E2F1在LUAD组织和细胞中的表达。通过CCK-8、集落形成和Transwell测定测试MELTF/E2F1对LUAD细胞增殖、迁移和侵袭的影响。通过双荧光素酶报告基因测定和ChIP测定来估计E2F1和MELTF之间的结合关系。采用蛋白质印迹法检测不同处理组Notch信号通路相关蛋白的表达。结果：生物信息学分析和qRT-PCR结果显示，E2F1和MELTF分别在LUAD组织和细胞中高表达。双荧光素酶报告基因测定和ChIP测定确定了E2F1与MELTF的结合。通过生物信息学方法确定MELTF可丰富Notch信号通路。在细胞实验中，MELTF被证明可以促进LUAD细胞的恶性进展，并促进NOTCH1和HES1蛋白的表达，但RO4929097抵消了MELTF对细胞的影响。救援分析证实，E2F1通过Notch信号通路激活MELTF以促进LUAD的进展。结论：我们的研究结果表明，E2F1通过Notch信号活性激活MELTF，从而促进LUAD的进展。因此，MELTF成为治疗LUAD的可行靶点。

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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.