MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.

Youwei Zhu, Jiangning Gu, Ying Li, Chenghong Peng, Minmin Shi, Xuelong Wang, Gang Wei, Ouyang Ge, Di Wang, Bosen Zhang, Jian Wu, Yiming Zhong, Baiyong Shen, Hao Chen

Journal: Cancer letters 2017;412():59-68

PMID: 28987387

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Abstract

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.

Address: 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; Research Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; Institute for Experimental Endocrinology, Charité́-Universita¨tsmedizin Berlin, D-13353 Berlin, Germany. Electronic address: [email protected].; Department of Scientific Research, Eyes & ENT Hospital of Fudan University, Shanghai, China. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].; 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. Electronic address: [email protected].

DOI: 10.1016/j.canlet.2017.09.044