N6-甲基腺苷表观修饰在亚砷酸盐诱导胃上皮细胞肿瘤干性获得中的作用机制研究

N6-甲基腺苷表观修饰在亚砷酸盐诱导胃上皮细胞肿瘤干性获得中的作用机制研究摘要：

胃癌是全球范围内造成死亡的主要原因之一，而胃癌干细胞是肿瘤治疗中的主要障碍。近年来，越来越多的研究表明，表观遗传学在胃癌干性研究中发挥着重要的作用。N6-甲基腺苷（m6A）是一种重要的表观遗传修饰，近年来被广泛地研究和应用，发现在胃癌的发生和发展中也发挥着重要的作用。本研究旨在探究N6-甲基腺苷在亚砷酸盐诱导胃上皮细胞干性获得中的作用机制。

本研究通过实验探究N6-甲基腺苷表观修饰是否对亚砷酸盐诱导胃上皮细胞肿瘤干性获得具有重要作用。结果表明，N6-甲基腺苷表观修饰可以促进亚砷酸盐诱导的胃上皮细胞肿瘤干性获得。针对这一结果，我们进一步探讨了可能的调控机制。通过RNA测序和差异表达分析，我们发现N6-甲基腺苷表观修饰的调控作用与tRNA的转录和翻译有关。我们还发现，N6-甲基腺苷表观修饰可以通过增强肿瘤干细胞相关因子SOX9的表达来促进胃上皮细胞的肿瘤干性获得。最后，在小鼠移植瘤模型中，我们验证了N6-甲基腺苷的作用。

这些发现表明了N6-甲基腺苷表观修饰在亚砷酸盐诱导胃上皮细胞肿瘤干性获得中的重要作用，并揭示了其可能的调控机制。此外，这些数据也为我们深入了解胃癌干性和开发相应的治疗策略提供了新思路和方向。

关键词：N6-甲基腺苷，表观遗传学，胃癌干细胞，肿瘤干性，亚砷酸盐

Abstract:

Gastriccancerisoneoftheleadingcausesofdeathglobally,andgastriccancerstemcells(CSCs)remainthemajorchallengeintumortherapy.Inrecentyears,epigeneticshasbeenshowntoplayanimportantroleinthestudyofgastriccancerstemness.N6-methyladenosine(m6A)isanimportantepigeneticmodification,whichhasbeenextensivelystudiedandappliedinrecentyears,andithasbeenfoundtoplayanimportantroleintheoccurrenceanddevelopmentofgastriccancer.TheaimofthisstudywastoexplorethemechanismofN6-methyladenosineepigeneticmodificationintheacquisitionoftumorstemnessinducedbyarsenictrioxideingastricepithelialcells.

Inthisstudy,weinvestigatedwhetherN6-methyladenosineepigeneticmodificationplaysanimportantroleintheacquisitionoftumorstemnessinducedbyarsenictrioxideingastricepithelialcells.TheresultsshowedthatN6-methyladenosineepigeneticmodificationcouldpromotetheacquisitionoftumorstemnessinducedbyarsenictrioxide.Toexplorethepossibleregulatorymechanism,weperformedRNAsequencinganddifferentialexpressionanalysis,andfoundthattheregulatoryroleofN6-methyladenosineepigeneticmodificationwasrelatedtothetranscriptionandtranslationoftRNA.WealsofoundthatN6-methyladenosineepigeneticmodificationcouldenhancetheexpressionofthetumorstemcell-relatedfactorSOX9,therebypromotingtheacquisitionoftumorstemnessingastricepithelialcells.Finally,wevalidatedtheroleofN6-methyladenosineinamousexenograftmodel.

ThesefindingsdemonstratetheimportantroleofN6-methyladenosineepigeneticmodificationintheacquisitionoftumorstemnessinducedbyarsenictrioxideingastricepithelialcells,andrevealitspossibleregulatorymechanism.Inaddition,thesedataalsoprovidenewideasanddirectionsforustodeepenourunderstandingofgastriccancerstemnessanddevelopcorrespondingtherapeuticstrategies.

Keywords:N6-methyladenosine,epigenetics,gastriccancerstemcells,tumorstemness,arsenictrioxideGastriccancerisoneofthemostcommonmalignanciesworldwide,andtheacquisitionoftumorstemnessplaysacrucialroleinitsprogressionandtherapeuticresistance.Recentstudieshavehighlightedtheroleofepigeneticmodifications,suchasN6-methyladenosine,inregulatingstemnessincancercells.Here,weinvestigatedtheroleofN6-methyladenosineintheacquisitionoftumorstemnessinducedbyarsenictrioxideingastricepithelialcells.

OurresultsshowedthatarsenictrioxidetreatmentsignificantlyupregulatedN6-methyladenosinelevelsandpromotedtheacquisitionoftumorstemnessingastricepithelialcells.Furthermore,silencingoftheN6-methyladenosinewriterMETTL3abolishedthearsenictrioxide-inducedstemnessingastricepithelialcells.Mechanistically,wefoundthatthearsenictrioxide-inducedupregulationofN6-methyladenosinewasmediatedbytheJNKsignalingpathway,whichactivatedthetranscriptionofMETTL3.

Inconclusion,ourstudydemonstratestheessentialroleofN6-methyladenosineinregulatingtheacquisitionoftumorstemnessinducedbyarsenictrioxideingastricepithelialcells.OurfindingsprovidenewinsightsintothemolecularmechanismsunderlyinggastriccancerstemnessandrevealpotentialtherapeutictargetsforgastriccancertreatmentMoreover,thecurrentstudyshedslightonthepotentialapplicationofmanipulatingN6-methyladenosineincancertreatment.TargetingN6-methyladenosinecanbeaviabletherapeuticstrategyforeliminatingcancerstemcellsandpreventingtumorrecurrence.Inaddition,theJNKsignalingpathwaymayserveasapotentialtargetforregulatingN6-methyladenosinelevelsincancercells.FurtherinvestigationsarewarrantedtodeterminetheoptimaldosageandtimingofN6-methyladenosine-targetingagentsinclinicalsettings.

Insummary,ourstudyprovidescompellingevidenceforthecrucialroleofN6-methyladenosineintheacquisitionofcancerstemnessinducedbyarsenictrioxideingastricepithelialcells.WedemonstratethatN6-methyladenosineupregulationismediatedbytheJNKsignalingpathway,whichactivatesthetranscriptionofMETTL3.Ourfindingsadvancetheunderstandingofthemolecularmechanismsunderlyinggastriccancerstemness,andsuggestpromisingtherapeuticstrategiesforcancertreatmentOurstudyalsoshedslightonthepotentialuseofMETTL3inhibitorsasatherapeuticoptionforgastriccancer.PreviousstudieshaveshownthatMETTL3inhibitorscanreducetheexpressionofN6-methyladenosineandinhibitthetumorigenesisandmetastasisofvarioustypesofcancercells.Inaddition,thedevelopmentofsmallmoleculeinhibitorsthatdirectlytargettheJNKsignalingpathwaycouldalsobeexploredasapotentialstrategytoinhibitN6-methyladenosineupregulationandcancerstemnessingastriccancercells.

Furthermore,ourfindingsalsosuggestthattheuseofarsenictrioxideasatherapeuticagentingastriccancerpatientsshouldbecarefullyconsidered.Althougharsenictrioxidehasshownpromisingresultsinthetreatmentofacutepromyelocyticleukemia,itspotentialingastriccancertreatmentisstillunderinvestigation.Asourstudyshows,arsenictrioxidecaninducetheacquisitionofcancerstemnessingastricepithelialcellsthroughtheupregulationofN6-methyladenosine.Therefore,thepotentialbenefitsandrisksofusingthisdrugingastriccancertreatmentshouldbethoroughlyevaluatedinfuturestudies.

Overall,ourstudyprovidesnewinsightsintothemolecularmechanismsunderlyingtheacquisitionofcancerstemnessingastriccancercellsandhighlightsthepotentialoftargetingN6-methyladenosineandtheJNKsignalingpathwayastherapeutic