MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes
MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes
复制标题
MiR-17-5p 通过破坏 RBL2/E2F4 抑制复合物来改变细胞周期特征，从而增强胰腺癌增殖
DOI：
10.1016/j.canlet.2017.09.044
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Chen, Hao
中科院分区：
文献类型：
--
作者：
Zhu, Youwei;Gu, Jiangning;Chen, Hao
miR-17-92簇的成员在各种癌症中上调，并作为致癌miRNA簇发挥作用。我们的研究表征了miR-17-92簇的成员miR-17- 5 p在调节胰腺癌细胞增殖中的新功能。我们的研究结果表明，miR-17- 5 p在胰腺癌中上调，并直接靶向视网膜母细胞瘤样蛋白2（RBL 2），一种属于Rb家族的肿瘤抑制因子。高水平的miR-17- 5 p和低水平的RBL 2与不良预后相关。RBL 2与转录因子E2 F4相互作用，并结合到E2 F靶基因的启动子区。通过miR-17- 5 p过表达破坏RBL 2/E2 F4复合物，将E2 F的活性从基因抑制转移到基因激活，从而诱导细胞进入周期和增殖。这些结果表明，miR-17- 5 p通过直接靶向RBL 2破坏RBL 2/E2 F4相关基因抑制复合物，促进胰腺导管腺癌细胞（PDAC）增殖，并改变体内和体外细胞周期谱。涉及miR-17- 5 p和RBL 2的新调控网络成为PDAC治疗的新靶点。(C)2017作者由爱思唯尔公司出版
The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment. (C) 2017 The Authors. Published by Elsevier B.V.