Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Research Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory of Computational Biology, CAS-MPG, Partner Institute of Computational Biology (PICB), Shanghai Institute for Biological Science (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
Cancer Lett. 2018 Jan 1;412:59-68. doi: 10.1016/j.canlet.2017.09.044. Epub 2017 Oct 4.
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.
miR-17-92 簇的成员在各种癌症中上调，并作为一组致癌 miRNA 发挥作用。我们的研究描绘了 miR-17-5p 的新功能，它是 miR-17-92 簇的成员，在调节胰腺癌中的细胞增殖方面发挥作用。我们的结果表明，miR-17-5p 在胰腺腺癌中上调，并直接靶向视网膜母细胞瘤样蛋白 2（RBL2），RBL2 是属于 Rb 家族的肿瘤抑制因子。miR-17-5p 水平高和 RBL2 水平低与预后不良相关。RBL2 与转录因子 E2F4 相互作用，并与 E2F 靶基因的启动子区域结合。miR-17-5p 过表达破坏 RBL2/E2F4 复合物，将 E2F 的活性从基因抑制转变为基因激活，从而诱导细胞周期进入和增殖。这些结果表明，miR-17-5p 通过直接靶向 RBL2 破坏 RBL2/E2F4 相关基因抑制复合物，促进胰腺导管腺癌（PDAC）细胞的增殖，并改变体内和体外的细胞周期谱。涉及 miR-17-5p 和 RBL2 的新调控网络，作为 PDAC 治疗的新靶点出现。
