HIC1 and miR-23 ∼ 27 ∼ 24 clusters form a double-negative feedback loop in breast cancer

被引:37
作者
Wang, Yanbo [1 ]
Liang, Hongwei [1 ]
Zhou, Geyu [1 ]
Hu, Xiuting [1 ]
Liu, Zhengya [1 ]
Jin, Fangfang [1 ]
Yu, Mengchao [1 ]
Sang, Jianfeng [2 ]
Zhou, Yong [3 ]
Fu, Zheng [1 ]
Zhang, Chen-Yu [1 ]
Zhang, Weijie [4 ,5 ]
Zen, Ke [1 ]
Chen, Xi [1 ]
机构
[1] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Jiangsu Engn Res Ctr MicroRNA Biol & Biotechnol, NJU Adv Inst Life Sci NAILS,Sch Life Sci, 163 Xianlin Ave, Nanjing 210046, Jiangsu, Peoples R China
[2] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Thyroid & Breast Surg, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
[3] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Thorac & Cardiovasc Surg, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
[4] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Gen Surg, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
[5] Nanjing Med Univ, Drum Tower Clin Coll, Dept Gen Surg, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
TUMOR-SUPPRESSOR; MICRORNAS; CELL; HETEROGENEITY; STATISTICS; NETWORK; SWITCH;
D O I
10.1038/cdd.2016.136
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 similar to 27 similar to 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 similar to 27 similar to 24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR-23 similar to 27 similar to 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.
引用
收藏
页码:421 / 432
页数:12
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