GCN2-eIF2α通路促进肺癌发生的分子机制研究
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关键词：肺癌;GCN2-eIF2α通路；转录组学；癌症发生机制；靶向肿瘤治疗 中图分类号：R734.2 文献标志码：A DOI：10.3969/j.issn.1007-7146.2025.06.007
Abstract：The GCN2-eIF2α pathwayregulates cellgrowthandservesasakeycomponentof the integrated stressresponse （ISR）.Inmalignanttumors，cancercelsesideinamcroenironmentcharacterizedbychronichypoxiaandnutrientdepivation. Undersuch conditions，the levelofaminoacidcatabolismincreases，whichactivatestheGCN2-eIF2α pathwayand inhibits proteinsynthesis tmaintainthecellaromeostasisofcancercels.Intissdy，totalof9pairsof tssuesamplesiludng canceroustissues andtheir matchedadjacent normaltissues，werecollectedfrompatientsdiagnosed withnon-smallcellung cancer （NSCLC）.Acombined analysis using histology，transcriptomics，qRT-PCR，and Western bloting was performed to investigate the molecular mechanismbywhich the GCN2-eIF2αpathwayregulatescancercellproliferation.Resultsofparafn sectionsshowedthatinthetumortissuesoflung cancerpatients，alveolarcells weredenselypacked，alveolarseptawere narrow，anduclearstaining washeterogeneous，exhibtingtypicalmalignanthistopathologicalfeatures.Transcriptomicstudies revealed thatthe enrichedpathwaysanddiferentially expressed genesamong samples wereidentifiedbasedongene ontology （GO）and Kyoto encyclopedia of genes and genomes （KEGG）enrichment results fromthe transcriptome，which confirmed thattheGCN2-eIF2αpathwayplaysanimportantroleinlungcarcinogenesis.Furtherscreening was performedtoselectkey genes forvalidationatthe molecularand protein levels.qRT-PCRresults demonstrated that these genes wereexpreed in both cancerous and normal tissue cels，with their expresson levels mostly upregulated in cancerous tissue cells （P<0.05） ， whichwasconsistentwiththegeneabundanceanalysisresultsinthetranscriptome.Attheproteilevel，theexpressionlevels ofgeneral control nonderepressible2 kinase（GCN2） and eukaryotic translation initiation 2α （eIF2α） in cancerous tissues weresignificantlyhigherthanthose inadjacent normaltissues，indicatingthatthe GCN2-eIF2apathwayis implicatedinlung carcinogenesis.This study can provide a reference for eIF2a and GCN2 to serve as new therapeutic targets for tumors，and also propose the possibility of inhibiting cancer cell progression by suppressing GCN2-mediated phosphorylation of eIF2a ，thereby offeringasolutiontoaddressthelimitationsofcurrentanti-tumor therapies.
Key words： lung cancer; GCN2-eIF2α pathway; transcriptomics; cancer pathogenesis; targeted tumor therapy
（ActaLaserBiologySinica，2025，34（6）：530-540）
2024年的全国癌症报告显示，肺癌再次成为全球第一大癌，中国在癌症新增病例与死亡病例中均位列第—[1-4]。（剩余17804字）
