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酸盐是一种表观遗传修饰剂,可引起表皮细胞转化为介质细胞
Marco Sciacovelli1, Emanuel Gonçalves2, Timothy Isaac Johnson1
1Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
Nature
|September 1, 2016
概括
烟酸酶的损失导致烟酸的积累,促进了侵袭性癌. 通过抑制表观遗传调节剂,驱动上皮细胞转化为介质细胞,导致转移和不良结果.
科学领域:
- 分子生物学
- 癌症学
- 表观遗传学
背景情况:
- 烟酸酶 (FH) 的突变会导致遗传性肌肉瘤和细胞癌 (HLRCC).
- 缺乏FH的癌是侵袭性的,并早期转移,导致不良的临床结果.
- 在缺乏FH的细胞中积累的烟酸作为一种代谢物,抑制参与DNA和基因素脱甲基化的二氧化酶.
研究的目的:
- 研究FH缺乏细胞中的烟酸积累,表观遗传变化和瘤发生之间的联系.
- 阐明 fumarate 促进癌症侵袭性和转移的机制.
主要方法:
- 对FH缺乏和FH高水平的小鼠和人类细胞的分析.
- 对表皮细胞转化为介质细胞 (EMT) 标记物和迁移性质的评估.
- 对miR-200bc-429集群的Tet介导脱甲基化进行研究.
- 在癌患者中,FH损失,miR-200抑制,EMT特征和临床结果的相关性.
主要成果:
- FH的损失和随后的烟酸积累诱导EMT,增强细胞迁移和入侵.
- 富马酸抑制了miR- 200bc-429集群的Tet介导脱甲基化,导致与EMT相关的转录因子表达.
- 缺乏FH的癌呈现抑制的miR- 200和激活的EMT特征,与预后不佳相关.
结论:
- 酸盐积累是FH缺陷细胞癌中侵袭性特征的关键驱动因素.
- 该机制涉及通过抑制miR-200bc-429集群的Tet介导脱甲基化而引起的表观遗传重编.
- 针对烟酸积累或其下游效应可能为侵袭性HLRCC提供治疗策略.
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