MicroRNA-26a is a key regulon that inhibits progression and metastasis of c-Myc/EZH2 double high advanced hepatocellular carcinoma
MicroRNA-26a is a key regulon that inhibits progression and metastasis of c-Myc/EZH2 double high advanced hepatocellular carcinoma
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MicroRNA-26a是抑制c-Myc/EZH2双高晚期肝细胞癌进展和转移的关键调节子
DOI：
10.1016/j.canlet.2018.04.005
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Jia, Lintao
中科院分区：
文献类型：
--
作者：
Zhang, Xiang;Zhang, Xiao;Jia, Lintao
转录因子c-Myc是肝细胞癌(HCC5)的关键驱动因子，而多聚抑制复合体2(PRC2)亚单位EZH2是肝细胞癌的重要生物标志物。C-Myc通过招募PRO和诱导组蛋白H3赖氨酸27的甲基化来抑制肿瘤抑制基因的表观遗传。然而，它们在肝细胞癌中是如何被调控的仍然是个谜。我们在这里发现，microRNA-26a(miR-26a)通过靶向Wnt途径的辅活化子细胞周期蛋白依赖性激酶8(CDK8)来抑制经典的Wnt途径靶基因c-Myc；miR-26a也直接靶向并抑制EZH2。M1R26A2是肝细胞miR-26a转录本的主要来源，其表达受c-Myc/PrC2的抑制，从而形成c-Myc/miR-26a/CDK8调控回路。同时，miR-26a通过靶向p21激活的激酶2(PAK2)来抑制肝癌的迁移，PAK2是连接Rho GTP酶与细胞骨架重组的关键激酶。因此，体内miR-26a通过下调c-Myc、CDK8和PAK2的表达，显著抑制移植瘤的发展和原位肝细胞癌的转移。这些发现揭示了c-Myc和Wnt/β-catenin相互作用的新机制，该机制决定了肝癌的发病机制，并暗示了miRNA传递在靶向新发现的信号轴和治疗转移性肝癌方面的潜在适用性。(C)2018爱思唯尔B.V.保留所有权利。
The transcription factor c-Myc is a key driver for hepatocellular carcinomas (HCC5), while the poly-combrepressive complex 2 (PRC2) subunit EZH2 is an essential biomarker of HCC. c-Myc epigenetically silences tumor suppressors by recruiting PRO and inducing methylation of histone H3 lysine 27. However, it remains elusive how they are regulated in HCC. We found here that microRNA-26a (miR-26a) suppresses c-Myc, a classical Wnt pathway target gene, by targeting the Wnt pathway coactivator, cyclin-dependent kinase 8 (CDK8); miR-26a also directly targets and inhibits EZH2. The expression of M1R26A2, a predominant origin of miR-26a transcripts in hepatic cells, is repressed by c-Myc/PRC2, thereby forming a c-Myc/miR-26a/CDK8 regulatory circuit in HCC. Meanwhile, miR-26a suppresses migration of HCC by targeting p21-activated kinase 2 (PAK2), a critical kinase linking Rho GTPases to cytoskeleton reorganization. Consequently, in vivo delivery of miR-26a remarkably suppressed the development of xenograft HCC and metastasis of orthotopic HCC by downregulating c-Myc, CDK8 and PAK2. These findings unraveled a novel mechanism of c-Myc and Wnt/beta-catenin interplay that dictates HCC pathogenesis, and have implications for the potential applicability of miRNA delivery in targeting the newly identified signaling axis and treating metastatic HCCs. (C) 2018 Elsevier B.V. All rights reserved.