MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer.
MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer.
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DOI：
10.3390/jcm4091713
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发表时间：
2015-08-26
影响因子：
3.9
通讯作者：
Selaru FM
中科院分区：
文献类型：
--
作者：
An F;Olaru AV;Mezey E;Xie Q;Li L;Piontek KB;Selaru FM
与正常肝脏相比，肝癌组织中microRNA(MiR)的表达水平经常发生深刻的变化。在这项研究中，我们评估了miR-224在人肝癌和CCA中的表达，以及它的下游靶点和影响途径。我们发现miR-224在大量的人类CCA中上调，类似于它在人类肝细胞癌中的上调。为了研究miR-224在肝癌和CCA中的作用，我们在细胞中增强了miR-224的表达。MRNA阵列和独创性路径分析(IPA)-确定了miR-224下游的假定分子和路径。典型地，我们报告了miR-224的增强表达增加了正常胆管细胞、CCA细胞系和肝癌细胞系的生长速度。此外，我们以一种公正的方式发现，miR-224影响的主要生物学过程之一是Gap1(G1)到合成(S)转换检查点的释放。接下来，我们确定了p21、p15和CCNE1作为miR-224的下游靶点，并证实了协同下调导致视网膜母细胞瘤(RB)磷酸化增加，从而导致G1/S检查点释放。我们的数据表明miR-224是细胞周期进程的主要调节者，其过度表达导致G1/S检查点释放，进而加速细胞生长。
Profound changes in microRNA (miR) expression levels are frequently found in liver cancers compared to the normal liver. In this study, we evaluate the expression of miR-224 in human HCC and CCA, as well as its downstream targets and affected pathways. We show that miR-224 is upregulated in a large cohort of human CCA, similar to its upregulation in human HCC. For the purpose of studying the roles of miR-224 in HCC and CCA, we enforced miR-224 expression in cells. mRNA arrays followed by Ingenuity Pathway Analysis (IPA)-identified putative molecules and pathways downstream of miR-224. Phenotypically, we report that enforced expression of miR-224 increases the growth rate of normal cholangiocytes, CCA cell lines, and HCC cell lines. In addition, we identified, in an unbiased fashion, that one of the major biologic processes affected by miR-224 is Gap1 (G1) to Synthesis (S) transition checkpoint release. We next identified p21, p15, and CCNE1 as downstream targets of miR-224 and confirmed the coordinated downregulation results in the increased phosphorylation of Retinoblastoma (Rb) with resulting G1/S checkpoint release. Our data suggest that miR-224 is a master regulator of cell cycle progression, and that its overexpression results in G1/S checkpoint release followed by accelerated cell growth.