The miR-486-5p plays a causative role in prostate cancer through negative regulation of multiple tumor suppressor pathways
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Yang Yang1,2, Changwei Ji1,2, Suhan Guo4, Xin Su5, Xiaozhi Zhao1,2, Shiwei Zhang1,2, Guangxiang Liu1,2, Xuefeng Qiu1,2, Qing Zhang1,2, Hongqian Guo1,2 and Huimei Chen1,3
1Department of Urology, Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Institute of Urology, Nanjing University, Nanjing 210008, China
2School of Medicine, Nanjing University, Nanjing 210093, China
3Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210002, China
4School of Public Health, Nanjing Medical University, Nanjing 211166, China
5Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
Huimei Chen, email: [email protected]
Hongqian Guo, email: [email protected]
Keywords: prostate cancer, miR-486-5p, cancer driver, oncogenic pathway, transcription factor
Received: December 20, 2016 Accepted: June 27, 2017 Published: August 24, 2017
MicroRNAs have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Aberrant miR-486-5p expression is frequently found in human cancers. Here we showed a significant overexpression of miR-486-5p in prostate cancer compared with that in normal tissue and cells, and we proposed that altered expression of miR-486-5p in the prostate contributed to prostate cancer. Firstly, miR-486-5p inhibition expression reduced prostate cancercell proliferation, migration, and colonization in vitro and prostate tumor development in vivo. Moreover, we integrated RNA sequencing and target genes prediction, and systemically identified miR-486-5p candidate target genes. We conducted an experiment verifying that miR-486-5p drives tumorigenesis by directly targeting multiple negative regulators, which were involved in PTEN/PI3K/Akt, FOXO, and TGF-b/Smad2 signaling. Finally, we demonstrated that hypoxia-inducible factor-1a and TCF-12 are located at the miR-486-5p promoter, which stimulates the transcription of miR-486-5p itself. Collectively, our findings unveil miR-486-5p as a powerful prostate cancer driver that coordinates the activation of multiple oncogenic pathways and demonstrates some stimulators, which mediate the miR-486-5p signaling pathway and may be targeted for therapy.
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