{"title":"缺氧诱导的HIF-1α通过靶向GAB2促进非小细胞肺癌的肿瘤发生","authors":"Xunxia Zhu , Xiaoyong Shen , Xiaoyu Chen, Xuelin Zhang, Wen Gao","doi":"10.1016/j.mrfmmm.2025.111917","DOIUrl":null,"url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is a lethal disease with high morbidity and mortality rates. HIF-1α is confirmed to be involved in NSCLC. However, the detailed mechanism of its role remains unclear. NCI-H226 and SK-MES-1 cell lines were used to explore the mechanisms by which hypoxia affects the progression of NSCLC <em>in vitro</em>. The cellular functions were detected by transwell. The expressions of key biomarkers were examined by Real-time quantitative reverse transcription PCR (qRT-PCR) and Western Blot assays. The RNA sequencing analysis was used to explore the downstream targets of HIF-1α. Luciferase and Chromatin immunoprecipitation (ChIP) assays confirmed the interaction between HIF-1α and GAB2. What’s more, the xenograft model was used to investigate the effect of GAB2 <em>in vivo</em>. Hypoxia promoted the migration and invasion capabilities of NCI-H226 and SK-MES-1 cells. RNA sequencing analysis revealed that the expression of GAB2 is dramatically altered under a hypoxic environment. The bioinformatics analysis implied that the differentially expressed genes (DEGs) were enriched in the MEK/ERK signaling pathway and the significantly expressed GAB2 was associated with HIF-1α. Functionally, GAB2 regulated migration and invasion capabilities in vitro and facilitated tumor growth and lung metastasis of NSCLC <em>in vivo</em>. What’s more, luciferase and ChIP assays further demonstrated that HIF-1α could bind to GAB2<strong>.</strong> Hypoxia-induced HIF-1α enhanced tumor growth and lung metastasis in NSCLC by targeting GAB2, which might provide novel insights into GAB2 as a potential therapeutic target for NSCLC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111917"},"PeriodicalIF":1.9000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hypoxia-induced HIF-1α enhanced the tumorigenesis in non-small cell lung cancer by targeting GAB2\",\"authors\":\"Xunxia Zhu , Xiaoyong Shen , Xiaoyu Chen, Xuelin Zhang, Wen Gao\",\"doi\":\"10.1016/j.mrfmmm.2025.111917\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Non-small cell lung cancer (NSCLC) is a lethal disease with high morbidity and mortality rates. HIF-1α is confirmed to be involved in NSCLC. However, the detailed mechanism of its role remains unclear. NCI-H226 and SK-MES-1 cell lines were used to explore the mechanisms by which hypoxia affects the progression of NSCLC <em>in vitro</em>. The cellular functions were detected by transwell. The expressions of key biomarkers were examined by Real-time quantitative reverse transcription PCR (qRT-PCR) and Western Blot assays. The RNA sequencing analysis was used to explore the downstream targets of HIF-1α. Luciferase and Chromatin immunoprecipitation (ChIP) assays confirmed the interaction between HIF-1α and GAB2. What’s more, the xenograft model was used to investigate the effect of GAB2 <em>in vivo</em>. Hypoxia promoted the migration and invasion capabilities of NCI-H226 and SK-MES-1 cells. RNA sequencing analysis revealed that the expression of GAB2 is dramatically altered under a hypoxic environment. The bioinformatics analysis implied that the differentially expressed genes (DEGs) were enriched in the MEK/ERK signaling pathway and the significantly expressed GAB2 was associated with HIF-1α. Functionally, GAB2 regulated migration and invasion capabilities in vitro and facilitated tumor growth and lung metastasis of NSCLC <em>in vivo</em>. What’s more, luciferase and ChIP assays further demonstrated that HIF-1α could bind to GAB2<strong>.</strong> Hypoxia-induced HIF-1α enhanced tumor growth and lung metastasis in NSCLC by targeting GAB2, which might provide novel insights into GAB2 as a potential therapeutic target for NSCLC.</div></div>\",\"PeriodicalId\":49790,\"journal\":{\"name\":\"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis\",\"volume\":\"831 \",\"pages\":\"Article 111917\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S002751072500020X\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S002751072500020X","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Hypoxia-induced HIF-1α enhanced the tumorigenesis in non-small cell lung cancer by targeting GAB2
Non-small cell lung cancer (NSCLC) is a lethal disease with high morbidity and mortality rates. HIF-1α is confirmed to be involved in NSCLC. However, the detailed mechanism of its role remains unclear. NCI-H226 and SK-MES-1 cell lines were used to explore the mechanisms by which hypoxia affects the progression of NSCLC in vitro. The cellular functions were detected by transwell. The expressions of key biomarkers were examined by Real-time quantitative reverse transcription PCR (qRT-PCR) and Western Blot assays. The RNA sequencing analysis was used to explore the downstream targets of HIF-1α. Luciferase and Chromatin immunoprecipitation (ChIP) assays confirmed the interaction between HIF-1α and GAB2. What’s more, the xenograft model was used to investigate the effect of GAB2 in vivo. Hypoxia promoted the migration and invasion capabilities of NCI-H226 and SK-MES-1 cells. RNA sequencing analysis revealed that the expression of GAB2 is dramatically altered under a hypoxic environment. The bioinformatics analysis implied that the differentially expressed genes (DEGs) were enriched in the MEK/ERK signaling pathway and the significantly expressed GAB2 was associated with HIF-1α. Functionally, GAB2 regulated migration and invasion capabilities in vitro and facilitated tumor growth and lung metastasis of NSCLC in vivo. What’s more, luciferase and ChIP assays further demonstrated that HIF-1α could bind to GAB2. Hypoxia-induced HIF-1α enhanced tumor growth and lung metastasis in NSCLC by targeting GAB2, which might provide novel insights into GAB2 as a potential therapeutic target for NSCLC.
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.