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Cancer Cell:一物降一物!新研究揭示绕过突变抑癌基因,根除癌细胞新机制

2021-02-22 生物探索 生物探索

mtp53可抑制先天性免疫信号传导,从而导致免疫逃逸。

TP53是一种关键的抑癌基因,通常会通过DNA结合域中的错义突变而失活。这些错义突变通常会使p53丧失肿瘤抑制活性,同时产生可促进肿瘤进展的突变的p53(mtp53)蛋白。 mtp53的存在可增加染色体的不稳定性,导致肿瘤抑制基因的丢失和癌基因的扩增。

近日,来自美国斯托尼布鲁克大学Luis A Martinez课题的的研究人员在《Cancer Cell》上发表了题为Mutant p53 suppresses innate immune signaling to promote tumorigenesis的研究成果,发现mtp53可抑制先天性免疫信号传导,从而导致免疫逃逸。恢复TBK1信号可绕过mtp53并恢复免疫细胞的功能,根除癌细胞。

为了确定mtp53是否调节先天性免疫信号通路,研究人员首先在人乳腺癌细胞BT549(p53R249S)、MDA-MB-231(p53R280K)和胰腺细胞株MIA PaCa中下调mtp53的表达。结果表明,敲低mtp53可促进TBK1及其底物IRF3和STING磷酸化,在小鼠和人的细胞中都产生相似的现象。并且,在两种不同类型的正常人成纤维细胞,IMR-90和人包皮成纤维细胞中,过表达mtp53可降低TBK1及其底物IRF3和STING的磷酸化。这些结果表明mtp53阻断先天免疫信号通路的活性。

突变p53可抑先天性免疫

在肿瘤微环境中,TBK1/STING/IRF3通路向免疫细胞发出有关肿瘤细胞存在的信号。研究人员发现mtp53可阻断IRF3的核易位,抑制cGAS/STING/TBK1/IRF3通路的细胞先天性免疫反应,从而抑制IRF3诱导的细胞凋亡。mtp53还可干扰TBK1-STING-IRF3复合物的形成,在具有完整免疫系统的宿主中可抑制免疫监视,从而加速肿瘤的生长。敲减mtp53可促进CD3+、CD4+、CD8+细胞和NK细胞的浸润。

突变p53可抑制免疫监视,促进肿瘤生长

有意思的是,研究人员发现激活TBK1可抑制mtp53诱导的肿瘤生长,恢复免疫监视。也就是说,mtp53诱导先天性免疫信号失活,改变细胞因子的产生,导致免疫逃逸;但是,恢复TBK1信号足以绕过mtp53,从而恢复免疫细胞的功能,并根除癌细胞。

模式图

总的来说,该研究发现了一种新的机制,mtp53通过干扰细胞质DNA感应机制cGAS-STING-TBK1-IRF3的功能,抑制细胞自主和非细胞信号传导,从而促进癌细胞生长和逃避免疫监视。恢复TBK1信号可以绕过mtp53,重新恢复免疫细胞功能,激活免疫监视,根除癌细胞。该意义重大,p53的状态可以指导治疗,并提供了新的治疗靶点。

原始出处:

Monisankar Ghosh, et al. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cance cell, 2021.DOI:https://doi.org/10.1016/j.ccell.2021.01.003.

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    2021-03-10 风铃830
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  5. 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objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
    2021-03-07 维他命
  6. 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objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
    2021-05-20 1464657dm92暂无昵称

    学习

    0

  7. 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objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
    2021-02-24 yxch36
  8. 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topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Mon Aug 23 15:54:47 CST 2021, time=2021-08-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962461, encodeId=d949196246157, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Mar 07 20:54:47 CST 2021, time=2021-03-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=967286, encodeId=9fbd96e286ca, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=80265125884, createdName=1464657dm92暂无昵称, createdTime=Thu May 20 19:15:30 CST 2021, time=2021-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252764, encodeId=1f921252e640f, content=<a href='/topic/show?id=3efee1519b2' target=_blank style='color:#2F92EE;'>#癌细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71519, encryptionId=3efee1519b2, topicName=癌细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4cea26, createdName=yxch36, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1323255, encodeId=51971323255d8, content=<a href='/topic/show?id=9934549500e' target=_blank style='color:#2F92EE;'>#抑癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54950, encryptionId=9934549500e, topicName=抑癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7e622500011, createdName=12498484m46(暂无昵称), createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1373969, encodeId=c25c13e39696a, content=<a href='/topic/show?id=3644e1286f1' target=_blank style='color:#2F92EE;'>#癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71286, encryptionId=3644e1286f1, topicName=癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=926726, encodeId=9d92926e2662, content=👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
  9. [GetPortalCommentsPageByObjectIdResponse(id=1780799, encodeId=d4551e80799d9, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4016, encryptionId=517a4016ac, topicName=cancer cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=96f62500201, createdName=12498e67m28暂无昵称, createdTime=Thu Dec 02 13:54:47 CST 2021, time=2021-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1683712, encodeId=e7771683e12d1, content=<a href='/topic/show?id=c2fc6228167' target=_blank style='color:#2F92EE;'>#根除#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=62281, encryptionId=c2fc6228167, topicName=根除)], attachment=null, authenticateStatus=null, createdAvatar=null, 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topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Mon Aug 23 15:54:47 CST 2021, time=2021-08-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962461, encodeId=d949196246157, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Mar 07 20:54:47 CST 2021, time=2021-03-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=967286, encodeId=9fbd96e286ca, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=80265125884, createdName=1464657dm92暂无昵称, createdTime=Thu May 20 19:15:30 CST 2021, time=2021-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252764, encodeId=1f921252e640f, content=<a href='/topic/show?id=3efee1519b2' target=_blank style='color:#2F92EE;'>#癌细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71519, encryptionId=3efee1519b2, topicName=癌细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4cea26, createdName=yxch36, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1323255, encodeId=51971323255d8, content=<a href='/topic/show?id=9934549500e' target=_blank style='color:#2F92EE;'>#抑癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54950, encryptionId=9934549500e, topicName=抑癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7e622500011, createdName=12498484m46(暂无昵称), createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1373969, encodeId=c25c13e39696a, content=<a href='/topic/show?id=3644e1286f1' target=_blank style='color:#2F92EE;'>#癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71286, encryptionId=3644e1286f1, topicName=癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=926726, encodeId=9d92926e2662, content=👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
  10. [GetPortalCommentsPageByObjectIdResponse(id=1780799, encodeId=d4551e80799d9, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4016, encryptionId=517a4016ac, topicName=cancer cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=96f62500201, createdName=12498e67m28暂无昵称, createdTime=Thu Dec 02 13:54:47 CST 2021, time=2021-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1683712, encodeId=e7771683e12d1, content=<a href='/topic/show?id=c2fc6228167' target=_blank style='color:#2F92EE;'>#根除#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=62281, encryptionId=c2fc6228167, topicName=根除)], attachment=null, authenticateStatus=null, createdAvatar=null, 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topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Mon Aug 23 15:54:47 CST 2021, time=2021-08-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962461, encodeId=d949196246157, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Sun Mar 07 20:54:47 CST 2021, time=2021-03-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=967286, encodeId=9fbd96e286ca, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=79, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=80265125884, createdName=1464657dm92暂无昵称, createdTime=Thu May 20 19:15:30 CST 2021, time=2021-05-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252764, encodeId=1f921252e640f, content=<a href='/topic/show?id=3efee1519b2' target=_blank style='color:#2F92EE;'>#癌细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71519, encryptionId=3efee1519b2, topicName=癌细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4cea26, createdName=yxch36, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1323255, encodeId=51971323255d8, content=<a href='/topic/show?id=9934549500e' target=_blank style='color:#2F92EE;'>#抑癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54950, encryptionId=9934549500e, topicName=抑癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7e622500011, createdName=12498484m46(暂无昵称), createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1373969, encodeId=c25c13e39696a, content=<a href='/topic/show?id=3644e1286f1' target=_blank style='color:#2F92EE;'>#癌基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71286, encryptionId=3644e1286f1, topicName=癌基因)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Wed Feb 24 00:54:47 CST 2021, time=2021-02-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=926726, encodeId=9d92926e2662, content=👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210130/f777d0b91a25425ba588babbf050d6d1/328b4c90fd7741d090ece3b8f155fc70.jpg, createdBy=25525455713, createdName=牛, createdTime=Tue Feb 23 23:03:50 CST 2021, time=2021-02-23, status=1, ipAttribution=)]
    2021-02-23

    👍

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