乳腺癌如何适应缺氧微环境并转移
氧是生物体、组织及细胞生存不可或缺的重要物质，而缺氧却发生于90%的实体肿瘤。作为调控肿瘤发生发展的关键因素，缺氧是实体肿瘤生存微环境的重要标志。肿瘤微环境的高度异质性可诱导基因参与代谢重编程，而代谢重编程对肿瘤适应多变生存环境发挥重要作用。目前，乳腺癌细胞适应缺氧微环境的内在分子机制尚不明确。
年5月25日，常春藤旗下《治疗诊断学》在线发表中国医院李鑫妍、王梦申、王墨之、孙湘雨、姚礼彤、董浩然、宋永喜、徐莹莹等学者的研究报告，探讨了细胞内氧化还原代谢重编程对乳腺癌细胞在缺氧微环境中的适应和生存的影响，从线粒体代谢角度揭示了乳腺癌适应缺氧微环境的机制。
该研究通过对乳腺癌组织样本转录组二代测序，结合差异表达基因富集分析以及临床样本验证，筛选出与线粒体生物合成和线粒体代谢功能密切相关的基因线粒体核糖体蛋白MRPL52，证实肿瘤缺氧可诱导MRPL52表达升高，且MRPL52在乳腺癌中具有抗凋亡和促转移的生物学功能。
该研究通过对线粒体形态的观察，发现在缺氧条件下，MRPL52过表达的乳腺癌细胞中线粒体形态较对照组细胞更为完整，但是线粒体数量明显下降。MRPL52可提高乳腺癌细胞的线粒体自噬水平，从而稳定细胞内氧自由基，帮助乳腺癌细胞在缺氧微环境中更好地生存。MRPL52通过双向调节细胞内线粒体氧自由基的产生水平，帮助乳腺癌细胞抵抗过度氧化应激造成的细胞凋亡，同时介导氧自由基→Notch1-Snail信号通路的活化，促进乳腺癌的侵袭转移。
因此，该研究从氧化还原重编程角度揭示了乳腺癌耐受缺氧微环境的内环境机理，对新型治疗策略开发以及靶向治疗效果监控提供新证据。
Theranostics.May25;11(15):-.
HIF-1-inducedmitochondrialribosomeproteinL52:amechanismforbreastcancercellularadaptationandmetastaticinitiationinresponsetohypoxia.
LiX,WangM,LiS,ChenY,WangM,WuZ,SunX,YaoL,DongH,SongY,XuY.
TheFirstAffiliatedHospitalofChinaMedicalUniversity,Shenyang,Liaoning,China;ZhongshanHospital,FudanUniversity,Shanghai,China.
BACKGROUND:Hypoxiaisahallmarkofthephysicalmicroenvironmentofsolidtumors.Asakeyfactorthatregulatestumordevelopmentandprogression,hypoxiacanreprogramtheexpressionofmultiplegenes,whosebiologicalfunctionandmolecularmechanismincancerremainlargelyunclear.Themitochondrialribosomeproteinfamilyconsistsofnuclear-encodedmitochondrialproteinsthatareresponsibleforproteinsynthesisinthemitochondria.
METHODS:Ahigh-throughputRNAsequencingassaywascarriedouttoidentifydifferentiallyexpressedmRNAsbetweenbreastcancertissuesandadjacentnormaltissuesaswellasbreasttumorswithmetastasisandthosewithoutmetastasis.OurclinicalsamplesandTCGAdatabasewereanalyzedtoobservetheclinicalvalueofmitochondrialribosomeproteinL52(MRPL52)inhumanbreastcancer.PotenthypoxiaresponseelementsinthepromoterregionofMRPL52wereidentifiedandvalidatedbychromatinimmunoprecipitationandluciferasereporterassays.FunctionalexperimentswereperformedusingbreastcancercelllineswithMRPL52ectopicexpressionandknockdownculturedina20%or1%O2environment.
RESULTS:MRPL52expressionwasupregulatedinhumanbreastcancerandwassignificantlyassociatedwithaggressiveclinicopathologicalcharacteristicsandahighermetastaticriskofbreastcancerpatients.WefoundthattheoverexpressionofMRPL52inbreastcancerisinducedbyhypoxia-induciblefactor-1inresponsetohypoxicexposure.TheroleofMRPL52insuppressingapoptosisandpromotingmigrationandinvasionofhypoxicbreastcancercellswasdemonstratedbyourexperimentalevidence.Mechanistically,MRPL52promotedPTEN-inducedputativekinase1/Parkin-dependentmitophagytoremoveoxidativelydamagedmitochondriaandpreventuncontrolledreactiveoxygenspecies(ROS)generation,thusrepressingactivationofthemitochondrialapoptoticcascade.Additionally,MRPL52augmentedepithelial-mesenchymaltransition,migrationandinvasionofhypoxicbreastcancercellsbyactivatingtheROS-Notch1-Snailsignalingpathway.Benefitedfromthisbidirectionalregulatorymechanism,MRPL52isresponsibleformaintainingROSlevelsinawindowthatcaninducetumorigenicsignaltransductionwithoutcausingcytotoxicityinhypoxicbreastcancercells.
CONCLUSIONS:ThisworkelucidatesthemolecularmechanismbywhichMRPL52mediateshypoxia-inducedapoptoticresistanceandmetastaticinitiationofbreastcancer,andprovidesnewinsightsintotheinterplaybetweencancerandthetumormicroenvironment.
PMID:
PMCID:PMC
DOI:10./thno.
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