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Hepatology:厦门大学生科院发现肝癌诊断治疗新靶点

2016-11-20 生物通 万纹 生物通 万纹

厦门大学生命科学学院等处的研究人员首次阐明了YAP-TEAD通过调节HNF4α控制肝癌发生的分子机制,并通过给肝癌重新表达HNF4α可以完全抑制YAP-TEAD信号过度激活引发的肝细胞过度增殖,从而为肝癌的诊断和治疗提供了新的靶点。

厦门大学生命科学学院等处的研究人员首次阐明了YAP-TEAD通过调节HNF4α控制肝癌发生的分子机制,并通过给肝癌重新表达HNF4α可以完全抑制YAP-TEAD信号过度激活引发的肝细胞过度增殖,从而为肝癌的诊断和治疗提供了新的靶点。


这一研究成果在线公布在Hepatology杂志上,领导这一研究的是厦门大学李博安教授,李教授研究组主要从事Wnt信号通路的主要组份与调节因子在正常以及应激条件下,对于肿瘤发生、发展和组织发育、代谢过程的影响,并以此为基础进行肿瘤、遗传性疾病、代谢性疾病分子标志物的筛选。  

Hippo通路是近年发现的调节器官大小的新通路,而YAP是Hippo通路下游的主要效应分子,其异常表达与多种癌症的发生发展密切相关,因此YAP被认为是肿瘤治疗的潜在分子靶点。而肝细胞核因子4α(hepatocyte nuclear factor 4α, HNF4α)是肝细胞核因子受体超家族中的一员。研究表明YAP和HNF4α是促进肝细胞增殖/癌变与分化的两个最重要因子,然而两者之间的关系一直不明确。  

在这篇文章中,研究人员发现YAP1可以通过泛素化-蛋白酶体途径降解HNF4α,从而抑制HNF4α下游靶基因的表达;反过来HNF4α则通过与TEAD4竞争结合YAP1 而抑制YAP-TEAD的转录活性和下游靶基因的表达。  

重要的是,过表达HNF4α能够完全抑制YAP-TEAD诱导的肝癌细胞的增殖与干细胞扩张。这样,在YAP-TEAD信号与HNF4α之间形成一个双负反馈环,共同维持肝细胞增殖-分化平衡,而打破这种平衡会引起癌变。之后他们还在大鼠诱导肝癌模型和转基因/基因敲除小鼠肝癌模型中验证了这一假说。  

这项研究首次阐明了YAP-TEAD通过调节HNF4α控制肝癌发生的分子机制。同时该研究也表明,通过给肝癌重新表达HNF4α可以完全抑制YAP-TEAD信号过度激活引发的肝细胞过度增殖,从而为肝癌的诊断和治疗提供了新的靶点。  

此外,一些研究显示HNF4α表达下降与肝癌的一些侵袭性临床病理特征密切相关,预测着患者预后不良。在转移性肝癌中HNF4α水平更加低。体内外异位表达HNF4α可抑制肝癌细胞转移。一组研究人员发现异位HNF4α表达是通过一种IKK非依赖性的机制抑制了RelA (p65)表达及和核易位,损害了NF-кB激活,这证实HNF4-NF-κB反馈环调控了肝癌进展。

作者简介:  

李博安 教授,博士生导师  
1986年,第四军医大学,医学学士学位;  
1996年,上海肿瘤研究所,生物化学与分子生物学博士学位;  
1998至2006年,德国和美国先后任博士后和高级研究员;  
2006年1月至今,厦门大学生命科学学院,闽江学者特聘教授,博士生导师。  
2012年至今,厦门大学生命科学学院副院长,分子诊断教育部工程研究中心副主任。  

1986, B. Med. The Fourth Military Medical University;   
1996, Ph.D. Shanghai Cancer Institute;   
1998-1999, Postdoctoral Fellow, Max-Planck Institute for Biochemistry, Germany;   2000-2004, Postdoctoral Fellow, University of California Irvine;   
2004-2006, Senior Researcher, University of California Irvine;   
2006-Present, Professor, Xiamen University School of Life Sciences.   
2012-Present, Deputy Dean, Xiamen University School of Life Sciences.   

研究领域(Research Area)  

wnt信号通路在正常组织发育和肿瘤形成过程中发挥重要作用。我们实验室的兴趣在于,研究该信号通路的主要组份与调节因子在正常以及应激条件下,对于肿瘤发生、发展和组织发育、代谢过程的影响;并以此为基础进行肿瘤、遗传性疾病、代谢性疾病分子标志物的筛选,建立分子诊断新方法、新技术,涉及到表观遗传学、干细胞生物学、分子诊断等生物学前沿领域。  

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    2017-05-02 xqptu
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    2016-11-22 lsndxfj
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    2016-11-22 gwc384
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  7. [GetPortalCommentsPageByObjectIdResponse(id=1660654, encodeId=6d12166065429, content=<a href='/topic/show?id=803c3e216cf' target=_blank style='color:#2F92EE;'>#厦门#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37216, encryptionId=803c3e216cf, topicName=厦门)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a25130440, createdName=xqptu, createdTime=Tue May 02 02:26:00 CST 2017, time=2017-05-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1910069, encodeId=6dbd1910069d9, content=<a href='/topic/show?id=21574368886' target=_blank style='color:#2F92EE;'>#大学生#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=43688, encryptionId=21574368886, topicName=大学生)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3883266, createdName=yykkxiaodou, createdTime=Sun Oct 29 19:26:00 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1288186, encodeId=69f012881868c, content=<a href='/topic/show?id=f10658e342d' target=_blank style='color:#2F92EE;'>#新靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58734, encryptionId=f10658e342d, topicName=新靶点)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=acc3210, createdName=lsndxfj, createdTime=Tue Nov 22 12:26:00 CST 2016, time=2016-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1423625, encodeId=1dd514236256e, content=<a href='/topic/show?id=9ece91631bd' target=_blank style='color:#2F92EE;'>#诊断治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=91631, encryptionId=9ece91631bd, topicName=诊断治疗)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=5afb3820115, createdName=feifers, createdTime=Tue Nov 22 12:26:00 CST 2016, time=2016-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1426686, encodeId=742014266863d, content=<a href='/topic/show?id=221d685172' target=_blank style='color:#2F92EE;'>#EPA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6851, encryptionId=221d685172, topicName=EPA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4a9b4077760, createdName=gwc384, createdTime=Tue Nov 22 12:26:00 CST 2016, time=2016-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1517359, encodeId=bff1151e35956, content=<a href='/topic/show?id=817b64646b3' target=_blank style='color:#2F92EE;'>#治疗新靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=56, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64646, encryptionId=817b64646b3, topicName=治疗新靶点)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=251911073486, createdName=12498f1em11(暂无昵称), createdTime=Tue Nov 22 12:26:00 CST 2016, time=2016-11-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=157222, encodeId=586a15e22204, content=YAP-TEAD通过调节HNF4α控制肝癌发生的分子机制, beContent=null, objectType=article, channel=null, level=null, likeNumber=91, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4bfa83595, createdName=jetleo, createdTime=Mon Nov 21 09:28:24 CST 2016, time=2016-11-21, status=1, ipAttribution=)]
    2016-11-21 jetleo

    YAP-TEAD通过调节HNF4α控制肝癌发生的分子机制

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