Genome Medicine :揭示非编码RNA在非小细胞肺癌进展和肿瘤免疫中的重要作用

2020-09-06 枫叶 iNature

长的非编码RNA(lncRNA)在各种癌症类型的肿瘤发生和转移中极为复杂。尽管如此,lncRNA在非小细胞肺癌(NSCLC)中的详细分子机制仍不是不确定。

长的非编码RNA(lncRNA)在各种癌症类型的肿瘤发生和转移中极为复杂。尽管如此,lncRNA在非小细胞肺癌(NSCLC)中的详细分子机制仍不是不确定。

2020年9月2日,武汉大学健康学院孙承操副教授、李得加教授和何启强教授课题组题共同合作在Genome Medicine 在线发表题为“FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway”的研究论文,该研究揭示了LINC00301在NSCLC临床标本、细胞和动物水平中的致癌作用,详细阐述了LINC00301在NSCLC肿瘤发生、发展、转移和免疫抑制微环境形成中的具体作用和分子调控机制,为NSCLC的肿瘤发生和免疫治疗提供了新的认识。结合LNA技术, LINC00301具备作为NSCLC诊断治疗靶点的潜能。

非小细胞肺癌(NSCLC)是全球癌症死亡的首要诱因,因此,阐明NSCLC的发生和发展机制,提高NSCLC的诊断和治疗迫在眉睫。长链非编码RNA(lncRNA)是一类长度大于200个核苷酸单位(nt)的不具备完整蛋白编码能力的RNA,长期以来被认为是基因“噪音”。随着人类基因组计划和二代测序的兴起,lncRNA在人类疾病尤其是癌症中所扮演的角色正被逐渐揭露。最近的研究发现他们广泛参与了多种癌症的病理生理过程,并有望作为临床预后或诊断标志物。随着锁核酸(Locked Nucleic Acid, LNA)技术的发展,lncRNA同时具备成为临床治疗靶标的潜能。

LINC00301与EZH2蛋白之间相互结合位点的确定

在本次研究中,研究组首次发现并报道了一个全新的lncRNA, LINC00301,其在NSCLC肿瘤样本和细胞系中特异性显着高表达,并与NSCLC病人的预后密切相关。体外和体内实验表明,LINC00301在NSCLC中促进细胞增殖、迁移和侵袭,抑制细胞周期阻滞、凋亡。

机制研究发现,转录因子FOXC1特异性地介导了NSCLC中LINC00301的表达。通过RNA原位杂交实验(FISH)发现LINC00301同时存在于NSCLC的细胞质和细胞核中,但细胞核中LINC00301的比值高于细胞质中所占的比值,故而推测LINC00301将同时在胞浆和胞核处发挥调控作用。

通过生物信息学预测和RNA分子生物学实验验证,发现LINC00301的第83-123 核苷酸位点可直接与调味增强子同源物2 (EZH2)的第612-727氨基酸位点特异性的结合,LINC00301将与EZH2形成复合体并募集后者富集于ELL蛋白相关因子2 (EAF2)的启动子上,促进EAF2基因启动子的第?1395-??1388 核苷酸位点发生H3K27me3,从而抑制EAF2的转录表达。而考虑到EAF2能够直接结合稳定von Hippel-Lindau (pVHL) 蛋白,因此,在NSCLC细胞中,下调的EAF2通过调控pVHL增加HIF1α的表达。

此外,LINC00301在细胞质内还可以作为miR-1276的竞争内源性RNA (ceRNA),缓解miR-1276对HIF1α的翻译抑制,最终也起到上调NSCLC细胞中HIF1α的表达。与此同时, LINC00301通过上调HIF1α信号途径促进NSCLC细胞分泌TGF-β, 后者募集并增加调节性T细胞(regulatory T cell, Treg)在肿瘤微环境的富集,降低效应性CD8+ Granzyme B+ T细胞在肿瘤中的数量,在NSCLC中形成免疫抑制微环境。

综上所述,本研究揭示了LINC00301在NSCLC临床标本、细胞和动物水平中的致癌作用,详细阐述了LINC00301在NSCLC肿瘤发生、发展、转移和免疫抑制微环境形成中的具体作用和分子调控机制,为NSCLC的肿瘤发生和免疫治疗提供了新的认识。结合LNA技术, LINC00301具备作为NSCLC诊断治疗靶点的潜能。

长链非编码RNA LINC00301在非小细胞肺癌(NSCLC)中的作用模式图

文章受到国家自然科学基金(81802285)、博士后创新人才支持计划(BX201700178)、中国博士后科学基金(2017M620340)、湖北省卫计委医学科研基金(WJ2019Q039)、中央高校专项基础研究基金(2015305020202,2042018kf0025)、武汉市卫计委医学科研基金(WG18Q01)、武汉大学人才启动基金、武汉大学健康学院自主科研基金(ZZKY0014)以及职业危害识别与控制湖北省重点实验室开放基金(OHIC2017Y02)的支持。健康学院孙承操副教授、2017级博士研究生朱伟和武汉市职业病防治院李淑隽医师为共同第一作者,孙承操副教授、李得加教授和何启强教授为共同通讯作者。本研究同时受到了德克萨斯大学M.D. Anderson肿瘤中心Liuqing Yang教授和Chunru Lin教授的重要指导意见。

原始出处:

Cheng-Cao Sun, Wei Zhu, Shu-Jun Li, et al.FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway.Genome Med. 2020 Sep 2;12(1):77. doi: 10.1186/s13073-020-00773-y.

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topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1584777, encodeId=75191584e77b6, content=<a href='/topic/show?id=83f5e9250e9' target=_blank style='color:#2F92EE;'>#编码#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79250, encryptionId=83f5e9250e9, topicName=编码)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b10a17056098, createdName=12498f6em12暂无昵称, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610690, encodeId=c3a31610690f4, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=)]
    2021-01-07 jeanqiuqiu
  4. 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attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=bada4796040, createdName=yinzhangyong, createdTime=Thu Nov 12 10:38:08 CST 2020, time=2020-11-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=883751, encodeId=e21a883e5133, content=为啥都往外面发, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=b5925394177, createdName=萧山yd, createdTime=Wed Sep 09 00:16:56 CST 2020, time=2020-09-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577740, encodeId=9e7815e77403a, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1584777, encodeId=75191584e77b6, content=<a href='/topic/show?id=83f5e9250e9' target=_blank style='color:#2F92EE;'>#编码#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79250, encryptionId=83f5e9250e9, topicName=编码)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b10a17056098, createdName=12498f6em12暂无昵称, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610690, encodeId=c3a31610690f4, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=)]
    2020-12-11 kalseyzl
  5. 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  6. 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channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Tue Sep 08 02:22:52 CST 2020, time=2020-09-08, status=1, ipAttribution=)]
    2020-11-12 yinzhangyong

    这个好!!!

    0

  7. 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    2020-09-09 萧山yd

    为啥都往外面发

    0

  8. 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对于MET外显子14跳跃突变的晚期非小细胞肺癌患者,Tepotinib治疗应答率在50%左右,最常见的3级以上不良事件为外周水肿

PD-1单抗Opdivo联合贝伐单抗和化疗:显着改善非小细胞肺癌患者的无进展生存期

与安慰剂组相比,Opdivo组合组在无进展生存期(PFS)的主要终点方面显示出统计学上的显着改善,并且未发现新的安全问题。

NEJM:肺癌治疗进展对死亡率的影响

2013-2016年,美国非小细胞肺癌患者的死亡率大幅下降,存活率大幅提高。随着治疗进展,发病率的降低,特别是靶向治疗的广泛使用是非小细胞肺癌患者死亡率下降的重要因素

NEJM:Selpercatinib用于RET融合阳性非小细胞肺癌患者的治疗

对于RET融合阳性非小细胞肺癌患者,Selpercatinib具有显著且持久的疗效