Cell Death Dis:新型亲和分子通过靶向EB病毒LMP2A蛋白N末端结构域抑制鼻咽癌细胞增殖

2020-04-17 QQY MedSci原创

EB病毒(EBV),也称为人伽马疱疹病毒(HHV-4),在人类中非常普遍,90%以上的3-5岁幼儿曾感染该病毒,在全球95%以上的成年人中检测到其特异的血清抗体,已知与多种癌症的发生密切相关。

EB病毒(EBV),也称为人伽马疱疹病毒(HHV-4),是一种DNA病毒,由爱泼斯坦及巴尔于19641年在地方性的伯基特淋巴瘤(BL)患者的肿瘤细胞培养物中发现。这种病毒在人类中非常普遍,90%以上的3-5岁幼儿曾感染该病毒,在全球95%以上的成年人中检测到其特异的血清抗体。

目前已知几种人类癌症,如BL、鼻咽癌(NPC)、霍奇金淋巴瘤(HL)及胃癌,均已证明与EBV感染有关。EBV潜伏感染引起的NPC是一种恶性肿瘤,具有明显的地理分布,在东南亚,尤其是在中国南部地区,患病率较高。众所周知,在鼻咽癌癌变过程中两种EBV潜伏膜蛋白(LMP1/LMP2A)的持续表达起着关键作用。因此,靶向LMP1/LMP2A蛋白并阻断LMP1/LMP2A介导的信号通路或可作为治疗NPC患者的一种方法。作为一种新型的小分子的(6.5 kDa)亲和力蛋白,亲和分子已被证实可以靶向特定的分子,并可充当影像学或治疗药物研究中的强有力的通用工具。

在该研究中,研究人员通过筛选噬菌体展示肽库,鉴定了三个与EBV病毒LMP2A蛋白的N末端结构域结合的亲和分子(ZLMP2A-N85、ZLMP2A-N110和ZLMP2A-N252),并通过表面等离振子共振(SPR)实验、间接免疫荧光实验、共免疫沉淀实验以及内外源的近红外小动物荧光成像实验证实了这三种分子对于LMP2A的N末端结构域的高亲和力及高特异性。
 

此外,靶向该N末端结构域的亲和分子可以显著降低C666-1、CNE-2Z及B95-8这几种EBV阳性细胞系的活性。进一步的研究表明,亲和分子ZLMP2A-N110可以抑制AKT、GSK-3β及β-catenin信号通路蛋白的磷酸化水平,导致β-catenin的核转运过程受到抑制。之后伴随着c-Myc癌基因的表达水平的下降,其可能是由于NPC衍生细胞系的活性降低造成的。

总而言之,该研究鉴定了三个新颖的与EB病毒LMP2A蛋白N末端结构域结合的亲和分子。在EBV相关鼻咽癌的分子成像及靶向治疗中,这些分子具有巨大的开发潜力。

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  4. 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ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1926359, encodeId=0b0a192635905, content=<a href='/topic/show?id=0c72e85900c' target=_blank style='color:#2F92EE;'>#结构域#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=78590, encryptionId=0c72e85900c, topicName=结构域)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=734374, createdName=gjsgj, createdTime=Thu Dec 24 07:13:27 CST 2020, time=2020-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252685, encodeId=6893125268512, 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=0, 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=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1531579, encodeId=fd3515315e949, content=<a href='/topic/show?id=770e5e9457' target=_blank style='color:#2F92EE;'>#Death#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5794, encryptionId=770e5e9457, topicName=Death)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=32e312278742, createdName=cy0328, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1540957, encodeId=5b41154095e8b, content=<a href='/topic/show?id=ba2ee78630b' target=_blank style='color:#2F92EE;'>#细胞增殖#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77863, encryptionId=ba2ee78630b, topicName=细胞增殖)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f58613291856, createdName=晓辰, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1555947, encodeId=e08a155594e93, content=<a href='/topic/show?id=74211096079' target=_blank style='color:#2F92EE;'>#LMP2A蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10960, encryptionId=74211096079, topicName=LMP2A蛋白)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=)]
    2021-01-23 docwu2019
  5. 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  6. [GetPortalCommentsPageByObjectIdResponse(id=1236514, encodeId=a06d1236514d9, content=<a href='/topic/show?id=16826468b2' target=_blank style='color:#2F92EE;'>#EB病毒#</a><a href='/topic/show?id=c3f910342343' target=_blank style='color:#2F92EE;'>#鼻咽癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6468, encryptionId=16826468b2, topicName=EB病毒), TopicDto(id=103423, encryptionId=c3f910342343, topicName=鼻咽癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Thu Aug 04 08:47:41 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871674, encodeId=0bab18e1674d8, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, 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ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1926359, encodeId=0b0a192635905, content=<a href='/topic/show?id=0c72e85900c' target=_blank style='color:#2F92EE;'>#结构域#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=78590, encryptionId=0c72e85900c, topicName=结构域)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=734374, createdName=gjsgj, createdTime=Thu Dec 24 07:13:27 CST 2020, time=2020-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252685, encodeId=6893125268512, 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=0, 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=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1531579, encodeId=fd3515315e949, content=<a href='/topic/show?id=770e5e9457' target=_blank style='color:#2F92EE;'>#Death#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5794, encryptionId=770e5e9457, topicName=Death)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=32e312278742, createdName=cy0328, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1540957, encodeId=5b41154095e8b, content=<a href='/topic/show?id=ba2ee78630b' target=_blank style='color:#2F92EE;'>#细胞增殖#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77863, encryptionId=ba2ee78630b, topicName=细胞增殖)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f58613291856, createdName=晓辰, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1555947, encodeId=e08a155594e93, content=<a href='/topic/show?id=74211096079' target=_blank style='color:#2F92EE;'>#LMP2A蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10960, encryptionId=74211096079, topicName=LMP2A蛋白)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=)]
    2020-12-24 gjsgj
  7. 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ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1926359, encodeId=0b0a192635905, content=<a href='/topic/show?id=0c72e85900c' target=_blank style='color:#2F92EE;'>#结构域#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=78590, encryptionId=0c72e85900c, topicName=结构域)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=734374, createdName=gjsgj, createdTime=Thu Dec 24 07:13:27 CST 2020, time=2020-12-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1252685, encodeId=6893125268512, 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=0, 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=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1531579, encodeId=fd3515315e949, content=<a href='/topic/show?id=770e5e9457' target=_blank style='color:#2F92EE;'>#Death#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5794, encryptionId=770e5e9457, topicName=Death)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=32e312278742, createdName=cy0328, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1540957, encodeId=5b41154095e8b, content=<a href='/topic/show?id=ba2ee78630b' target=_blank style='color:#2F92EE;'>#细胞增殖#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77863, encryptionId=ba2ee78630b, topicName=细胞增殖)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f58613291856, createdName=晓辰, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1555947, encodeId=e08a155594e93, content=<a href='/topic/show?id=74211096079' target=_blank style='color:#2F92EE;'>#LMP2A蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10960, encryptionId=74211096079, topicName=LMP2A蛋白)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=)]
    2020-04-19 yxch36
  8. [GetPortalCommentsPageByObjectIdResponse(id=1236514, encodeId=a06d1236514d9, content=<a href='/topic/show?id=16826468b2' target=_blank style='color:#2F92EE;'>#EB病毒#</a><a href='/topic/show?id=c3f910342343' target=_blank style='color:#2F92EE;'>#鼻咽癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6468, encryptionId=16826468b2, topicName=EB病毒), TopicDto(id=103423, encryptionId=c3f910342343, topicName=鼻咽癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211210/ede9c51184aa4f54ae6c1164cfb8eeac/967dbf3eff2943c7bf3ccfec3a776ab0.JPG, createdBy=a33789389, createdName=病毒猎手, createdTime=Thu Aug 04 08:47:41 CST 2022, time=2022-08-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871674, encodeId=0bab18e1674d8, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, 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createdName=yxch36, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1531579, encodeId=fd3515315e949, content=<a href='/topic/show?id=770e5e9457' target=_blank style='color:#2F92EE;'>#Death#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5794, encryptionId=770e5e9457, topicName=Death)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=32e312278742, createdName=cy0328, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1540957, encodeId=5b41154095e8b, content=<a href='/topic/show?id=ba2ee78630b' target=_blank style='color:#2F92EE;'>#细胞增殖#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77863, encryptionId=ba2ee78630b, topicName=细胞增殖)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f58613291856, createdName=晓辰, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1555947, encodeId=e08a155594e93, content=<a href='/topic/show?id=74211096079' target=_blank style='color:#2F92EE;'>#LMP2A蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10960, encryptionId=74211096079, topicName=LMP2A蛋白)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=a12645, createdName=智智灵药, createdTime=Sun Apr 19 14:13:27 CST 2020, time=2020-04-19, status=1, ipAttribution=)]
    2020-04-19 cy0328
  9. 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  10. 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