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Nature Commun:癌基因?错!其实它也是抑癌基因

2018-08-08 小通 生物通

许多肿瘤过表达PLK1基因,于是,研究人员就认为它是促瘤剂。最近,西班牙癌症研究中心(CNIO)和德国癌症研究中心(DKFZ)的研究人员《Nature Communications》发文,报道在一些乳腺肿瘤中,PLK1的功能反而是抑制癌症。


许多肿瘤过表达PLK1基因,于是,研究人员就认为它是促瘤剂。最近,西班牙癌症研究中心(CNIO)和德国癌症研究中心(DKFZ)的研究人员《Nature Communications》发文,报道在一些乳腺肿瘤中,PLK1的功能反而是抑制癌症。

如此,科学家们必须对PLK1作为肿瘤靶向药物的原理进行回顾,因为它可能取决于要治疗的肿瘤类型——抑制它或者有用,或者起反作用。目前科学家已经发现,PLK1表达可以决定乳腺癌不同预后,这取决于肿瘤亚型。

PLK1基因对肿瘤细胞分裂和增殖必不可少。近年来,很多研究在多种肿瘤类型中发现PLK1过量表达,并且其过量表达与不良预后有关。因此,几十年来,Plk1一直被认为是致癌基因(oncogene)。随后,因为抑制Plk1活性可以诱导细胞肿瘤死亡被作为治疗靶点研究,事实上,已经有Plk1抑制剂进入高阶临床试验阶段。
然而,奇怪的是,PLK1的致癌性质却从未被正式证实过,换句话说,到现在还没有进行实验证明PLK1过度表达确实有助于肿瘤发展。

马德里CNIO和海德堡DKFZ的研究人员合作的初期目标其实是为了验证PLK1过度表达对肿瘤的促进作用。为此,他们修改了小鼠的基因组,诱导动物过量表达PLK1。可是,他们却注意到,这些基因工程动物并没有比正常小鼠产生更多肿瘤。于是,他们让这些小鼠与乳腺组织表达Her2或H-Ras致癌基因的小鼠(一种侵袭性乳腺肿瘤模型)杂交。研究人员预期后代小鼠的癌症发病率应该比较高,但结果却出乎意料:致癌基因和过量表达PLK1的加乘效果是后代小鼠肿瘤的发病率急剧下降!

“我们马上意识到这其中肯定存在被忽视的重要事件,”文章共同一作Guillermo de Cárcer说。“事实上,我们已经证明,PLK1不仅致癌,而且它也抑癌。”

作为乳腺癌预后指标,研究人员查阅了乳腺数据库以寻找Plk1过表达与患者预后之间的联系。他们发现“Plk1表达在不同癌症亚型中所指示的预后情况完全不同。”
在Her2阳性肿瘤中,PLK1过量表达具有较好预后,而在雌激素受体(ER+)表达阳性的患者中,结果完全相反。这篇文章不仅描述了PLK1作为肿瘤抑制因子的新作用,还进一步坚定了这种抑制效应的分子机制。

研究人员发现,PLK1过表达增加了细胞染色体数量,当细胞开始分裂时,导致它们不能正确地分离染色体。

如果Plk1是一个肿瘤抑制因子,那么此前基于它的治疗方案就需要重新研究。不过,本文通讯作者Marcos Malumbres 则认为Plk1抑制剂仍不失为一种有效的控制肿瘤的选择。“Plk1是一个肿瘤抑制因子而不是一个致癌因子,这并不意味着Plk1抑制剂对抗击肿瘤没有效果,”他说。“许多细胞增殖步骤都可以靶向抗癌,尽管没有致癌活性,它的存在也会导致特定癌细胞的增殖分离。”

Guillermo de Cárcer强调,将Plk1基因作为肿瘤生物标志物和治疗靶点时,需要考虑肿瘤类型。
 
原始出处:

Guillermo de Cárcer, et al.Plk1 overexpression induces chromosomal instability and suppresses tumor development.Nature Communications 9, 3012 August 2018 | OPEN

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    2019-04-29 liuli5079
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  4. 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    2018-08-16 kafei

    学习了谢谢

    0

  5. 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    2018-08-11 15938038573红旗飘飘

    已学习并已分享

    0

  6. 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  7. 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encodeId=d83033e538bd, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/09/9d6ae4a345db0c5799f866ac5743fbc0.jpg, createdBy=0ba62073690, createdName=GZphD9, createdTime=Thu Aug 09 12:36:24 CST 2018, time=2018-08-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=337485, encodeId=e1a133e48509, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Thu Aug 09 08:32:57 CST 2018, time=2018-08-09, status=1, ipAttribution=), 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  8. 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encodeId=d83033e538bd, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/09/9d6ae4a345db0c5799f866ac5743fbc0.jpg, createdBy=0ba62073690, createdName=GZphD9, createdTime=Thu Aug 09 12:36:24 CST 2018, time=2018-08-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=337485, encodeId=e1a133e48509, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Thu Aug 09 08:32:57 CST 2018, time=2018-08-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=337482, encodeId=f96f33e4829d, content=将Plk1基因作为肿瘤生物标志物和治疗靶点时,需要考虑肿瘤类型, beContent=null, objectType=article, channel=null, level=null, likeNumber=105, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdgSW0vVibEHQRlKXLlvMibvcHmy5ibwM7Luib2am6ywX6FqBrXibF8k7JVEzriaOSghltmYz1nomRd6TgSp2Yj9xHGAY/0, createdBy=9b2f2045808, createdName=haige, createdTime=Thu Aug 09 08:21:16 CST 2018, time=2018-08-09, status=1, ipAttribution=)]
    2018-08-09 GZphD9

    学习了

    0

  9. 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encodeId=d83033e538bd, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/09/9d6ae4a345db0c5799f866ac5743fbc0.jpg, createdBy=0ba62073690, createdName=GZphD9, createdTime=Thu Aug 09 12:36:24 CST 2018, time=2018-08-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=337485, encodeId=e1a133e48509, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=113, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfBfgWn9nXBgH1sNSiaOAKhsKpN40jDHQKqcRzovau5VibLvREN8uxnu9sKoScBicHSiaDMmbveibFdrBiaD4k4IOPwlG/0, createdBy=b5d11730951, createdName=Jackie Li, createdTime=Thu Aug 09 08:32:57 CST 2018, time=2018-08-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=337482, encodeId=f96f33e4829d, content=将Plk1基因作为肿瘤生物标志物和治疗靶点时,需要考虑肿瘤类型, beContent=null, objectType=article, channel=null, level=null, likeNumber=105, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdgSW0vVibEHQRlKXLlvMibvcHmy5ibwM7Luib2am6ywX6FqBrXibF8k7JVEzriaOSghltmYz1nomRd6TgSp2Yj9xHGAY/0, createdBy=9b2f2045808, createdName=haige, createdTime=Thu Aug 09 08:21:16 CST 2018, time=2018-08-09, status=1, ipAttribution=)]
    2018-08-09 Jackie Li

    学习

    0

  10. 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    2018-08-09 haige

    将Plk1基因作为肿瘤生物标志物和治疗靶点时,需要考虑肿瘤类型

    0

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