title: HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer.
abstract: MicroRNAs (miRNAs) have emerged as a major regulator of the initiation and progression of human cancers, including breast cancer. However, the cooperative effects and transcriptional regulation of multiple miRNAs, especially miRNAs that are present in clusters, remain largely undiscovered. Here we showed that all members of the miR-23~27~24 clusters are upregulated and function as oncogenes in breast cancer and simultaneously target HIC1. Furthermore, we found that HIC1 functions as a transcriptional repressor to negatively control the expression of miR-23~27~24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR-23~27~24 clusters can remarkably accelerate tumor growth, whereas restoration of HIC1 significantly blocks tumor growth in vivo. A mathematical model was created to quantitatively illustrate the regulatory circuit. Our finding highlights the cooperative effects of miRNAs in a cluster and adds another layer of complexity to the miRNA regulatory network. This study may also provide insight into the molecular mechanisms of breast cancer progression.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Geyu
authors.initials: G
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Xiuting
authors.initials: X
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Zhengya
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Thyroid and Breast Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Sang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.|Department of General Surgery, Drum Tower Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, Jiangsu, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions; D000626:Aminopeptidases / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D036382:Ephrin-A1 / Q000378:metabolism; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D016415:Sequence Alignment; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D036382:Ephrin-A1; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C501315:AOPEP protein, human; D000626:Aminopeptidases; D056564:Sirtuin 1