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中国学者破解乳腺癌对化疗耐药的关键机制和 [复制链接]

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  编者按:最新证据表明,癌症治疗耐药与上皮-间质转化之间存在分子学和表现型的相关性。既往研究已知微核糖核酸(miR)a过表达可以促使人乳腺癌细胞抗脱落凋亡并发生转移,但是miR-a对治疗耐药的作用尚不明确。


  年1月12日,英国《生物医学中心·癌症》在线发表医院肿瘤研究所以及医院邵志敏和狄根红等学者的研究报告,发现人乳腺癌miR-a通过拮抗肿瘤蛋白p53诱导核蛋白1(TP53INP1)与原癌基因酪氨酸蛋白激酶Yes相关蛋白(YAP1)引起化疗耐药。


  该研究通过体外化疗耐药miR-a模拟物或抑制剂转染乳腺癌细胞,通过定量实时PCR(qRT-PCR)评定乳腺癌术前化疗患者miR-a表达,通过萤光素酶法、细胞增殖法确定miR-a的靶点,及其促进治疗耐药的机制,通过生存分析评估miR-a的预后价值。


  结果发现:

异位miR-a表达促进乳腺癌细胞系对若干化疗药物耐药

抑制miR-a可以增强耐药癌细胞对吉西他滨化疗敏感性

miR-a过表达与乳腺癌患者术前化疗效果差和预后不良密切相关

抑制YAP1和TP53INP1基因表达可以表型模拟miR-a过表达效应并证实TP53INP1为miR-a的新靶点

乳腺癌细胞系miR-a表达与TP53INP1表达成反比


  因此,上述基础和临床研究结果表明,miR-a是乳腺癌化疗耐药的决定因素之一,miR-a过表达通过拮抗TP53INP1和YAP1引起乳腺癌化疗耐药,针对该靶点反其道而行之即可减少乳腺癌化疗耐药。

BMCCancer.Jan12;18(1):74.

MicroRNA-aconferschemoresistancebyantagonizingTP53INP1andYAP1inhumanbreastcancer.

YuSJ,YangL,HongQ,KuangXY,DiGH,ShaoZM.

CancerHospital/CancerInstitute,ShanghaiMedicalCollege,InstitutesofBiomedicalSciences,FudanUniversity,Shanghai,China.

BACKGROUND:Emergingevidencesuggestsmolecularandphenotypicassociationbetweentreatmentresistanceandepithelial-mesenchymaltransition(EMT)incancer.Comparedwiththewell-definedmoleculareventsofmiR-ainEMT,theroleofmiR-aintherapyresistanceremainstobeelucidated.

METHODS:BreastcancercellstransfectedwithmimicorinhibitorformiR-awasassayedforchemoresistanceinvitro.miR-aexpressionwasassessedbyquantitativereal-timePCR(qRT-PCR)inbreastcancerpatientstreatedwithpreoperativechemotherapy.Luciferaseassays,cellproliferationassaywereperformedtoidentifythetargetsofmiR-aandthemechanismbywhichitpromotestreatmentresistance.SurvivalanalysiswasusedtoevaluatetheprognosisvalueofmiR-a.

RESULTS:Inthisstudy,ourresultsshowedectopicexpressionofmiR-apromoteschemoresistanceinbreastcancercelllinestoseveralchemotherapeuticagents,whereasinhibitionofmiR-aenhancesgemcitabinechemosensitivityinresistancecancercells.WefoundoverexpressionofmiR-awascloselyassociatedwithpoorresponsetopreoperativechemotherapyandpoorprognosisinbreastcancerpatients.Furthermore,knockdownofYAP1andTP53INP1phenocopiedtheeffectsofmiR-aoverexpression,andconfirmedthatTP53INP1isanoveltargetofmiR-a.Remarkably,TP53INP1expressionisinverselycorrelatedwithmiR-aexpressioninBreastcancercelllines.Takentogether,theseclinicalandexperimentalresultsdemonstratethatmiR-aisadeterminantofchemoresistanceofbreastcancer.

CONCLUSIONS:UpregulatedmiR-aenhancestreatmentresistanceviaantagonizingTP53INP1andYAP1inbreastcancer.

KEYWORDS:Breastcancer;Chemoresistance;Preoperativechemotherapy;microRNA

PMID/p>

DOI:10./s---0

生物医学中心癌症

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