MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes. (1st January 2018)

• Record Type: Journal Article
• Authors: Zhu, Youwei; Gu, Jiangning; Li, Ying; Peng, Chenghong; Shi, Minmin; Wang, Xuelong; Wei, Gang; Ge, Ouyang; Wang, Di; Zhang, Bosen; Wu, Jian; Zhong, Yiming; Shen, Baiyong; Chen, Hao
• Is Part Of: Cancer letters. Volume 412(2018)
• Page Start: 59
• Page End: 68
• Publication Date: 2018-01-01
• Subjects: miR-17-5p -- RBL2 -- E2F4 -- Cell cycle -- Pancreatic cancer; CRF Chromatin remodeling factor -- DP Dimerization partner -- HDACs Histone deacetylases -- MuvB Multivulva class B -- PDAC Pancreatic ductal adenocarcinoma -- RBL2 Retinoblastoma-like protein2; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.09.044
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: miR-17-5p promotes pancreatic cancer proliferation by altering cell cycle profiles. miR-17-5p directly targets the 3′UTR of RBL2. RBL2 interacts directly with E2F4 and binds to promoter regions of the E2F target genes. A model in which miR-17-5p disrupts RBL2/E2F4-associated gene repression by targeting RBL2 is proposed.