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Cancer Cell：肝脏“保护神” 让慢性肝炎和肝癌快走开

2015-11-19 佚名 生物谷

NF-kB肝细胞癌RIPK1
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本文研究亮点：   与消除NEMO的作用不同，抑制肝实质细胞中的NF-kB不会引起自发性肝细胞癌   在特异性敲除肝实质细胞内NEMO的小鼠中，IKK2/NF-kB组成型激活能够防止肝损伤以及肝细胞癌发生   RIPK1激酶介导的肝细胞凋亡会驱动NEMO特异性敲除小鼠发生肝细胞癌   NEMO能够阻止RIPK1/FADD/Casp8复合体的

本文研究亮点：
 
与消除NEMO的作用不同，抑制肝实质细胞中的NF-kB不会引起自发性肝细胞癌
 
在特异性敲除肝实质细胞内NEMO的小鼠中，IKK2/NF-kB组成型激活能够防止肝损伤以及肝细胞癌发生
 
RIPK1激酶介导的肝细胞凋亡会驱动NEMO特异性敲除小鼠发生肝细胞癌
 
NEMO能够阻止RIPK1/FADD/Casp8复合体的形成，该复合体会诱导肝实质细胞凋亡
 
调节细胞存活，细胞死亡和炎症的信号途径在肝脏稳态平衡的维持以及慢性肝疾病和癌症的发生过程中都发挥着非常重要的作用。Caspase依赖性凋亡与RIPK依赖性程序性坏死（necroptosis）都是参与细胞程序性死亡的关键途径，这两条途径也参与一些疾病的发病机制。
 
在最近发表在国际学术期刊Cance Cell上的一篇文章中，来自德国的科学家对细胞凋亡如何参与脂肪性肝炎和肝细胞癌的发生进行了深入研究。
 
在这项研究中，研究人员发现RIPK1能够通过一种RIPK3非依赖性机制介导肝实质细胞凋亡，这会进一步触发慢性肝炎和肝细胞癌（HCC）的发生。研究发现RIPK1的这一作用依赖于它的激酶活性，同时还会受到NEMO分子参与的NF-kB依赖性途径和NF-kB非依赖性途径的共同调控。之前许多研究只证明NEMO分子可以激活NF-kB，但NEMO分子是否直接参与肝脏稳态维持以及肝脏疾病发生未有研究。
 
有研究表明肝脏实质细胞中缺失NEMO分子的小鼠会自发形成慢性肝炎以及HCC，因此推测NF-kB可能在肝脏疾病以及癌症发生中发挥抑制作用。为了对这一观点进行进一步验证，研究人员首先在肝实质细胞中特异性消除RelA, c-Rel和RelB以实现对NF-kB的完全抑制，结果并没有引起自发性HCC，这与NEMO敲除小鼠的表型并不吻合。随后研究人员在NEMO特异性敲除小鼠中组成型激活NF-kB，小鼠的肝脏得到了保护，没有发生肝脏细胞损伤和HCC。这就表明NEMO并非通过单一途径实现对小鼠肝脏的保护。
 
为了对下游分子机制进行探讨，研究人员利用Knock-in技术将失去酶活性的RIPK1导入NEMO特异性敲除小鼠体内，发现失去酶活性的RIPK1能够阻止肝脏细胞凋亡以及HCC的发生，而彻底消除RIPK1则会诱导肝实质细胞发生TRADD依赖性细胞凋亡，还会诱导肝脏肿瘤的形成。上述结果表明RIPK1可以通过其酶活性或作为支架蛋白这两种不同机制发挥功能。
 
总得来说，这些结果表明NEMO能够通过NF-kB依赖性和非依赖性途径抑制RIPK1酶活性驱动的肝实质细胞凋亡，这为脂肪性肝炎和肝细胞癌的未来治疗提供了新的理论基础，具有重要意义。

原文出处：
 

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    2016-08-25 维他命

    #CEL#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1959501, encodeId=ca18195950115, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, 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=Thu Aug 25 12:37:00 CST 2016, time=2016-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1674897, encodeId=afc716e489743, content=<a href='/topic/show?id=9c6b5362561' target=_blank style='color:#2F92EE;'>#慢性肝炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=53625, encryptionId=9c6b5362561, topicName=慢性肝炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6e1127134834, createdName=redcrab, createdTime=Tue Mar 08 14:37:00 CST 2016, time=2016-03-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1780664, encodeId=fb121e80664b3, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, 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=Wed Mar 30 02:37:00 CST 2016, time=2016-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869245, encodeId=8a3b186924552, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sun Jul 10 15:37:00 CST 2016, time=2016-07-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=43438, encodeId=362b43438eb, content=肝炎新方向么, beContent=null, objectType=article, channel=null, level=null, likeNumber=126, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8aa11659262, createdName=IIIi, createdTime=Fri Nov 20 08:03:00 CST 2015, time=2015-11-20, status=1, ipAttribution=)]
    2016-03-08 redcrab

    #慢性肝炎#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1959501, encodeId=ca18195950115, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, 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=Thu Aug 25 12:37:00 CST 2016, time=2016-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1674897, encodeId=afc716e489743, content=<a href='/topic/show?id=9c6b5362561' target=_blank style='color:#2F92EE;'>#慢性肝炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=53625, encryptionId=9c6b5362561, topicName=慢性肝炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6e1127134834, createdName=redcrab, createdTime=Tue Mar 08 14:37:00 CST 2016, time=2016-03-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1780664, encodeId=fb121e80664b3, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, 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=Wed Mar 30 02:37:00 CST 2016, time=2016-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869245, encodeId=8a3b186924552, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sun Jul 10 15:37:00 CST 2016, time=2016-07-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=43438, encodeId=362b43438eb, content=肝炎新方向么, beContent=null, objectType=article, channel=null, level=null, likeNumber=126, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8aa11659262, createdName=IIIi, createdTime=Fri Nov 20 08:03:00 CST 2015, time=2015-11-20, status=1, ipAttribution=)]
    2016-03-30 12498e67m28暂无昵称

    #cancer cell#

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1959501, encodeId=ca18195950115, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, 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=Thu Aug 25 12:37:00 CST 2016, time=2016-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1674897, encodeId=afc716e489743, content=<a href='/topic/show?id=9c6b5362561' target=_blank style='color:#2F92EE;'>#慢性肝炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=53625, encryptionId=9c6b5362561, topicName=慢性肝炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6e1127134834, createdName=redcrab, createdTime=Tue Mar 08 14:37:00 CST 2016, time=2016-03-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1780664, encodeId=fb121e80664b3, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, 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=Wed Mar 30 02:37:00 CST 2016, time=2016-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869245, encodeId=8a3b186924552, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sun Jul 10 15:37:00 CST 2016, time=2016-07-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=43438, encodeId=362b43438eb, content=肝炎新方向么, beContent=null, objectType=article, channel=null, level=null, likeNumber=126, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8aa11659262, createdName=IIIi, createdTime=Fri Nov 20 08:03:00 CST 2015, time=2015-11-20, status=1, ipAttribution=)]
    2016-07-10 zhaozhouchifen

    #Cell#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1959501, encodeId=ca18195950115, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, 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=Thu Aug 25 12:37:00 CST 2016, time=2016-08-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1674897, encodeId=afc716e489743, content=<a href='/topic/show?id=9c6b5362561' target=_blank style='color:#2F92EE;'>#慢性肝炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=53625, encryptionId=9c6b5362561, topicName=慢性肝炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=6e1127134834, createdName=redcrab, createdTime=Tue Mar 08 14:37:00 CST 2016, time=2016-03-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1780664, encodeId=fb121e80664b3, content=<a href='/topic/show?id=517a4016ac' target=_blank style='color:#2F92EE;'>#cancer cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, 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=Wed Mar 30 02:37:00 CST 2016, time=2016-03-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869245, encodeId=8a3b186924552, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sun Jul 10 15:37:00 CST 2016, time=2016-07-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=43438, encodeId=362b43438eb, content=肝炎新方向么, beContent=null, objectType=article, channel=null, level=null, likeNumber=126, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8aa11659262, createdName=IIIi, createdTime=Fri Nov 20 08:03:00 CST 2015, time=2015-11-20, status=1, ipAttribution=)]
    2015-11-20 IIIi

    肝炎新方向么

    0