J Hepatol:端粒酶,肝癌的新潜在治疗靶点!

2021-01-20 MedSci原创 MedSci原创

端粒酶激活是肝细胞癌(HCC)发展的最早事件。端粒长度(TL)受TERT(端粒逆转录酶)、TERC(端粒RNA组分)和多种蛋白组成的端粒复合物的调控。本研究旨在阐明肝癌发生过程中的端粒长度的变化及调控

端粒酶激活是肝细胞癌(HCC)发展的最早事件。端粒长度(TL)受TERT(端粒逆转录酶)、TERC(端粒RNA组分)和多种蛋白组成的端粒复合物的调控。本研究旨在阐明肝癌发生过程中的端粒长度的变化及调控。

研究人员测量了1502位患者(978例HCC)肿瘤组织和非肿瘤组织的端粒长度,并通过基因组、外显子组、靶向或RNA测序分析了TERT变异和表达与肝癌的临床和分子特征的相关性。此外,还在26种细胞系和移植瘤小鼠模型中评估了抗TERT反义寡核苷酸(ASO)的临床前活性。

肝端粒长度与年龄、纤维化、男性和酒精摄入相关

年龄、肝纤维化、男性和过度酒精摄入都是肝端粒消耗的独立决定因素。具有长端粒的肝发展而来的HCC通常是具有祖细胞特征和BAP1突变的TERT野生型。相反,具有短端粒的肝发展而来的HCC多为非增殖型HCC,且多富集体系TERT启动子突变。

TERT过表达和长端粒与HCC侵袭相关

HCC可通过多种机制激活TERT表达使端粒长度稳定在5.7Kb,在一个较窄的生物学范围内,类似于非肿瘤肝脏。在肿瘤中,长端粒是强侵袭性HCC的特征,与G3转录亚型、TP53变异和预后不良相关

抗TERT ASO的抗肿瘤活性

在HCC细胞系中,用反义寡核苷酸链沉默TERT在高增殖和分化不良的细胞中很有效。用反义寡核苷酸链处理了3-16周后,在12个细胞系中通过缩短端粒长度、DNA损伤和凋亡激活成功诱导细胞增殖停滞。反义寡核苷酸链在移植瘤小鼠模型中也获得了治疗效果。

总而言之,在HCC肿瘤发生过程中,端粒长度的维持是多样的,与肿瘤的进展和侵袭性相关。抗TERT ASO在HCC细胞系中的活性揭示了TERT的致瘤性和抗TERT ASO进入HCC临床试验的临床前基础。

原始出处:

Massih Ningarhari, et al. Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target. Journal of Hepatology. 20 November 2020.

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    2021-01-26 1257c336m18暂无昵称

    为啥发表不了漂亮

    0

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    2021-01-22 gwc384
  5. [GetPortalCommentsPageByObjectIdResponse(id=1895417, encodeId=7494189541e43, content=<a href='/topic/show?id=18ae64e21d3' target=_blank style='color:#2F92EE;'>#治疗靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64721, encryptionId=18ae64e21d3, topicName=治疗靶点)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55683, createdName=仁医06, createdTime=Wed Jun 16 10:02:46 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920105, encodeId=5cdc92010515, content=为啥发表不了漂亮, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01f52568974, createdName=1257c336m18暂无昵称, createdTime=Tue Jan 26 21:54:02 CST 2021, time=2021-01-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396106, encodeId=11ed139610603, content=<a href='/topic/show?id=017ce5693fe' target=_blank style='color:#2F92EE;'>#端粒酶#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=75693, encryptionId=017ce5693fe, topicName=端粒酶)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1427481, encodeId=f850142e48120, content=<a href='/topic/show?id=221d685172' target=_blank style='color:#2F92EE;'>#EPA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, 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=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918607, encodeId=ec4c91860e42, content=111111, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201215/e3e7faa007024c79aabbddd5f3c859e8/bbf4547d810244ab879ee1beefdd800b.jpg, createdBy=4b6a5155323, createdName=146a55a0m33暂无昵称, createdTime=Thu Jan 21 07:02:24 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1040343, encodeId=5ba910403435a, content=肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=留走人康, createdTime=Thu Jan 21 02:02:46 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918575, encodeId=73439185e544, content=端粒酶激活是肝细胞癌(HCC)发展的最早事件。, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Q3auHgzwzM4gCIdSaEkahCNuUWZv4iaKmqvUKHyKnBiarBM9RStQKBeV5Lh6GYYFiamdV5KlSfbLvmAgZTLtq81XA/0, createdBy=13511650672, createdName=言西早, createdTime=Wed Jan 20 23:13:42 CST 2021, time=2021-01-20, status=1, ipAttribution=)]
    2021-01-21 146a55a0m33暂无昵称

    111111

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=1895417, encodeId=7494189541e43, content=<a href='/topic/show?id=18ae64e21d3' target=_blank style='color:#2F92EE;'>#治疗靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64721, encryptionId=18ae64e21d3, topicName=治疗靶点)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55683, createdName=仁医06, createdTime=Wed Jun 16 10:02:46 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920105, encodeId=5cdc92010515, content=为啥发表不了漂亮, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01f52568974, createdName=1257c336m18暂无昵称, createdTime=Tue Jan 26 21:54:02 CST 2021, time=2021-01-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396106, encodeId=11ed139610603, content=<a href='/topic/show?id=017ce5693fe' target=_blank style='color:#2F92EE;'>#端粒酶#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=75693, encryptionId=017ce5693fe, topicName=端粒酶)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1427481, encodeId=f850142e48120, content=<a href='/topic/show?id=221d685172' target=_blank style='color:#2F92EE;'>#EPA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, 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=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918607, encodeId=ec4c91860e42, content=111111, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201215/e3e7faa007024c79aabbddd5f3c859e8/bbf4547d810244ab879ee1beefdd800b.jpg, createdBy=4b6a5155323, createdName=146a55a0m33暂无昵称, createdTime=Thu Jan 21 07:02:24 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1040343, encodeId=5ba910403435a, content=肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=留走人康, createdTime=Thu Jan 21 02:02:46 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918575, encodeId=73439185e544, content=端粒酶激活是肝细胞癌(HCC)发展的最早事件。, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Q3auHgzwzM4gCIdSaEkahCNuUWZv4iaKmqvUKHyKnBiarBM9RStQKBeV5Lh6GYYFiamdV5KlSfbLvmAgZTLtq81XA/0, createdBy=13511650672, createdName=言西早, createdTime=Wed Jan 20 23:13:42 CST 2021, time=2021-01-20, status=1, ipAttribution=)]
    2021-01-21 留走人康

    肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1895417, encodeId=7494189541e43, content=<a href='/topic/show?id=18ae64e21d3' target=_blank style='color:#2F92EE;'>#治疗靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64721, encryptionId=18ae64e21d3, topicName=治疗靶点)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55683, createdName=仁医06, createdTime=Wed Jun 16 10:02:46 CST 2021, time=2021-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=920105, encodeId=5cdc92010515, content=为啥发表不了漂亮, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01f52568974, createdName=1257c336m18暂无昵称, createdTime=Tue Jan 26 21:54:02 CST 2021, time=2021-01-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396106, encodeId=11ed139610603, content=<a href='/topic/show?id=017ce5693fe' target=_blank style='color:#2F92EE;'>#端粒酶#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=75693, encryptionId=017ce5693fe, topicName=端粒酶)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1427481, encodeId=f850142e48120, content=<a href='/topic/show?id=221d685172' target=_blank style='color:#2F92EE;'>#EPA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, 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=Fri Jan 22 14:02:46 CST 2021, time=2021-01-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918607, encodeId=ec4c91860e42, content=111111, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201215/e3e7faa007024c79aabbddd5f3c859e8/bbf4547d810244ab879ee1beefdd800b.jpg, createdBy=4b6a5155323, createdName=146a55a0m33暂无昵称, createdTime=Thu Jan 21 07:02:24 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1040343, encodeId=5ba910403435a, content=肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=留走人康, createdTime=Thu Jan 21 02:02:46 CST 2021, time=2021-01-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=918575, encodeId=73439185e544, content=端粒酶激活是肝细胞癌(HCC)发展的最早事件。, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Q3auHgzwzM4gCIdSaEkahCNuUWZv4iaKmqvUKHyKnBiarBM9RStQKBeV5Lh6GYYFiamdV5KlSfbLvmAgZTLtq81XA/0, createdBy=13511650672, createdName=言西早, createdTime=Wed Jan 20 23:13:42 CST 2021, time=2021-01-20, status=1, ipAttribution=)]
    2021-01-20 言西早

    端粒酶激活是肝细胞癌(HCC)发展的最早事件。

    0

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