ArticleJournal of experimental & clinical cancer research : CR2022
5'isomiR-183-5p|+2 elicits tumor suppressor activity in a negative feedback loop with E2F1.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 11 citations in OpenAlex.
- GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.Clinical epigenetics · 2026Article
- Targetome profile of hsa-miR-93-5p is resistant to isoform formation in prostate adenocarcinoma.PeerJ · 2026Article
- Selective arm-usage of pre-miR-1307 dysregulates angiogenesis and affects breast cancer aggressiveness.BMC biology · 2025Article
- IsomiRome analysis reveals dysregulation of 5' isomiRs during SARS-CoV-2 infection.Computational and structural biotechnology journal · 2025Article
- The crosstalk between non-coding RNAs and cell-cycle events: A new frontier in cancer therapy.Molecular therapy. Oncology · 2024Review
- The miR-183 Cluster: Biogenesis, Functions, and Cell Communication via Exosomes in Cancer.Cells · 2023Review
- MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies.American journal of cancer research · 2023Review
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Authors and funding
20 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundMicroRNAs (miRNAs) and isomiRs play important roles in tumorigenesis as essential regulators of gene expression. 5'isomiRs exhibit a shifted seed sequence compared to the canonical miRNA, resulting in different target spectra and thereby extending the phenotypic impact of the respective common pre-miRNA. However, for most miRNAs, expression and function of 5'isomiRs have not been studied in detail yet. Therefore, this study aims to investigate the functions of miRNAs and their 5'isomiRs.
methodsThe expression of 5'isomiRs was assessed in The Cancer Genome Atlas (TCGA) breast cancer patient dataset. Phenotypic effects of miR-183 overexpression in triple-negative breast cancer (TNBC) cell lines were investigated in vitro and in vivo by quantifying migration, proliferation, tumor growth and metastasis. Direct targeting of E2F1 by miR-183-5p|+2 was validated with a 3'UTR luciferase assay and linked to the phenotypes of isomiR overexpression.
resultsTCGA breast cancer patient data indicated that three variants of miR-183-5p are highly expressed and upregulated, namely miR-183-5p|0, miR-183-5p|+1 and miR-183-5p|+2. However, TNBC cell lines displayed reduced proliferation and invasion upon overexpression of pre-miR-183. While invasion was reduced individually by all three isomiRs, proliferation and cell cycle progression were specifically inhibited by overexpression of miR-183-5p|+2. Proteomic analysis revealed reduced expression of E2F target genes upon overexpression of this isomiR, which could be attributed to direct targeting of E2F1, specifically by miR-183-5p|+2. Knockdown of E2F1 partially phenocopied the effect of miR-183-5p|+2 overexpression on cell proliferation and cell cycle. Gene set enrichment analysis of TCGA and METABRIC patient data indicated that the activity of E2F strongly correlated with the expression of miR-183-5p, suggesting transcriptional regulation of the miRNA by a factor of the E2F family. Indeed, in vitro, expression of miR-183-5p was regulated by E2F1. Hence, miR-183-5p|+2 directly targeting E2F1 appears to be part of a negative feedback loop potentially fine-tuning its activity.
conclusionsThis study demonstrates that 5'isomiRs originating from the same arm of the same pre-miRNA (i.e. pre-miR-183-5p) may exhibit different functions and thereby collectively contribute to the same phenotype. Here, one of three isomiRs was shown to counteract expression of the pre-miRNA by negatively regulating a transcriptional activator (i.e. E2F1). We speculate that this might be part of a regulatory mechanism to prevent uncontrolled cell proliferation, which is disabled during cancer progression.
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