c—flip在凋亡增殖中的双向调节作用及与肿瘤预后和治疗关系的研究

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1、主望壁堕堕±整笈4期ChinJClinOncol2013，Vo1．40，No．24www．cjco．cn1573c—FLlP在凋亡增殖中的双向调节作用及与肿瘤预后和治疗关系的研究：l：臧凤琳综述孙保存审校摘要细胞型Fas相关死亡域样白介素一1p转换酶抑制蛋白(c—FLIP)在细胞凋亡和增殖信号通路中具有重要的调节作用。一方面通过与Caspase一8竞争性结合上游信号阻断凋亡通路，另一方面经酶切释放出p43一FLIP和p22一FLIP片段促进NF—KB、Ek等增殖信号通路，最终引发肿瘤发生发展、浸润转移。c—FLIP的双向调节作用与蛋白表达量、底物的亲和力和亚细胞定位密切相关。恶性肿瘤

2、中c—FLIP高表达使细胞逃逸机体免疫监视、耐受化疗药物杀伤以及抵抗TRAIL、FasL诱导的凋亡。本文初步阐释c-FLIP在不同的细胞微环境中对凋亡一增殖通路的双向调节作用及其分子机制，并对c—FLIP与恶性肿瘤预后、化疗和TRAIL生物治疗相关性进行综述，为肿瘤化疗耐药和TRAIL抵抗提供理论基础。关键词c—FLIP凋亡增殖预后肿瘤标志物doi：10．3969~．issn．1000—8179．20131080Researchprogressonthedualregulationofc-FLIPinapoptosisandproliferationandtherelationshi

3、pbetweenc．FLIPandtumorprognosis．chemotherapy,andTRAILtreatmentincancersFenglinZANG，BaocunSUNCorrespondenceto：BaocunSUN；E-mail：baocunsun@gmail．tomDepartmentofPathology,TianjinMedicalUniversityCancerInstituteandHospital，NationalClinicalResearchCenterofCancer,KeyLaboratoryofCancerPreventionandTher

4、apy,Tianjin，Tianjin300060，ChinaThisstudywassupposedbytheOutstandingYoungScientistProgramoftheNationalNaturalScienceFoundationofChina(No．81001020)AbstractCellularFas—associateddeathdomain-likeinterleukin-113-convertingenzymeinhibitoryprotein(c—FLIP)belongstothedeathefectordomainsuperfamily,which

5、isimportantinregulatingapoptosisandproliferation．c—FLIPinhibitstheextrinsicrecep—tor-mediatedapoptoticpathwaysandintrinsicmitochondrialapoptoticpathwaysthroughcompetitionwithcaspase-8forrecruitmenttoFas—associateddeathdomainprotein．Moreover,thecleavageproducts(i．e．，p43一FLIPfragmentandp22-FLIPfr

6、agment)directlyacti—vateNF-KB，Erksurvivalsignaling，andothernon—apoptoticsignalingpathways．Thec—FLIP(L)canfunctioneitherasananti—apoptoticmolecule，inawayanalogoustoc—FLIP(S)andc—FLIP(R)，orasapro—apoptoticmoleculetofacilitatetheactivationofcaspase-8atthedeath—inducedsignalingcomplex．Theidentified

7、dualfunctionalityofc-FLIPdependsonvariousfactors，includingitsexpressionlevel，interactionwithcaspase一8．anditssubcellularlocalization．c—FLIPisfrequentlyover-expressedinmanydifferenttumortypes，andcon—tributestotumorcellimmunesurveill