HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer
Open accessAbstract
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.
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Overexpression of the miR-23 functional cluster accelerates tumor growth, whereas recovery of HIC1 can significantly inhibit tumor growth.
“overexpression of the miR-23 functional cluster accelerates tumor growth, whereas the recovery of HIC1 can significantly inhibit tumor growth [82].”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [82]
All members of the miR-23-27-24 cluster are increased and act as oncogenes in breast cancer.
“all members of the miR-23-27-24 cluster are increased and act as oncogenes in breast cancer.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [82]
Regulation of miR-23 is not merely acting on target genes and downstream signaling pathways, but can also be directly regulated by the target gene, forming a regulatory feedback loop.
“This study indicates that the regulation of miR-23 is not merely acting on target genes and downstream signaling pathways, but can also be directly regulated by the target gene, forming a regulatory feedback loop.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [82]
The target gene HIC1 of the miR-23 functional cluster acts as a transcription inhibitor to negatively regulate their expression levels, forming a negative feedback loop.
“the target gene HIC1 of the miR-23 functional cluster also acts as a transcription inhibitor to negatively regulate their expression levels, forming a negative feedback loop.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [82]
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- Authors
- Wang, Y., Liang, H., Zhou, G., Hu, X., Liu, Z., Jin, F., Yu, M., Sang, J., Zhou, Y., Fu, Z., Zhang, C.-Y., Zhang, W., Zen, K., & Chen, X.
- Affiliations
- State Key Laboratory of Pharmaceutical Biotechnology (CN)
- Nanjing Drum Tower Hospital (CN)
- Corresponding author
- Zhang, Chen-Yu
- Zhang, Weijie
- Zen, Ke
- Chen, Xi
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2016-12-23
- Volume
- 24
- Issue
- 3
- Pages
- 421-432
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5344204
- OpenAlex
- W2566200459
- Cited by
- 38
- References
- 33
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 3
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (J1103512 and J1210026, 973 Program, 31271378, J1103512, 201302018, 2014CB542300, J1210026)
- Sun Yat-sen University
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province (201302018, BE2016737, J1103512, 31271378, 2014CB542300, No. BE2016737)
- National Key Research and Development Program of China (201302018, J1210026, 31271378, 2014CB 542300, J1103512, No. 2014CB542300)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Keywords
- HIC1, miRNA clusters, double-negative feedback loop, breast cancer, oncogenic microRNA, transcriptional repression, tumor growth, miRNA regulatory network
- MeSH terms
- Aminopeptidases, Animals, Base Sequence, Binding Sites, Breast Neoplasms, Cell Movement, Female, Humans, Promoter Regions, Genetic, Sequence Alignment, Mice, SCID, Apoptosis, 3' Untranslated Regions, RNA Interference, MicroRNAs, Ephrin-A1, Cell Line, Tumor, Mice, Rats, Kruppel-Like Transcription Factors, Sirtuin 1, MCF-7 Cells
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