CyclinD1 inhibits dicer and crucial miRNA expression by chromatin modification to promote the progression of intrahepatic cholangiocarcinoma
CyclinD1 inhibits dicer and crucial miRNA expression by chromatin modification to promote the progression of intrahepatic cholangiocarcinoma
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CyclinD1通过染色质修饰抑制dicer和关键miRNA表达促进肝内胆管癌进展
DOI：
10.1186/s13046-019-1415-5
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发表时间：
2019-10-07
影响因子：
11.3
通讯作者：
Chen, Yongjun
中科院分区：
文献类型：
--
作者：
Qi, Yongqiang;Wang, Da;Chen, Yongjun
研究背景CyclinD 1是细胞周期的重要调控因子，它可以调节microRNA成熟的关键调节因子Dicer的表达。然而，关于CyclinD 1如何调控Dicer和miRNA的表达以及与肝内胆管癌（intrahepatic cholangiocarcinoma，ICC）发生发展的关系尚不清楚。通过免疫沉淀、ChIP测序、BSP和荧光素酶报告基因分析，在诱导CyclinD 1过表达或沉默和Dicer沉默后，确定CyclinD 1调节Dicer和相对miRNA表达的潜在机制。CyclinD 1和/或Dicer沉默对ICC生长的影响在vivo.ResultsUp-regulated CyclinD 1与下调Dicer在ICC组织中的表达和ICC患者的总体生存较差。CyclinD 1与细胞核H3 K9 me 3和SUV 39 H1相互作用，并与Dicer启动子结合，以增加其在ICC细胞中的CpG岛甲基化。在功能上，CyclinD 1沉默抑制ICC细胞的恶性肿瘤，这部分减轻了ICC细胞中的Dicer沉默。结论CyclinD 1通过染色质修饰抑制Dicer表达，从而抑制miR-1914 - 5 p/miR-541 - 5 p的表达，正反馈促进CyclinD 1和CDK 6的表达，促进ICC的进展。
BackgroundCyclinD1 is crucial for cell cycling and can regulate the expression of Dicer, a crucial regulator of microRNA maturation. However, little is known on how CyclinD1 regulates Dicer and miRNA expression, and the progression of intrahepatic cholangiocarcinoma (ICC).MethodsThe expression of CyclinD1 and Dicer in non-tumor cholangiocytes, ICC cells and tissues as well as their association with clinicopathological characteristics and survival were examined. The potential mechanisms by which CyclinD1 regulates Dicer and relative miRNA expression were determined by immunoprecipitation, ChIP sequence, BSP and luciferase reporter assays following induction of CyclinD1 over-expression or silencing and Dicer silencing. The impact of CyclinD1 and/or Dicer silencing on the growth of ICC was tested in vivo.ResultsUp-regulated CyclinD1 was associated with down-regulated Dicer expression in ICC tissues and poorer overall survival in patients with ICC. CyclinD1 interacted with the nuclear H3K9me3 and SUV39H1 and bound to the Dicer promoter to increase its CpG island methylation in ICC cells. Functionally, CyclinD1 silencing inhibited the malignancy of ICC cells, which were mitigated partially by Dicer silencing in ICC cells. Dicer silencing down-regulated miR-1914-5p and miR-541-5p expression, which targeted and promoted CyclinD1 and CDK6 expression in ICC cells.ConclusionsOur findings uncover that CyclinD1 inhibits Dicer expression by chromatin modification to reduce miR-1914-5p/miR-541-5p expression, which positively-feedback enhances CyclinD1 and CDK6 expression and progression of ICC.