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Updated: Sep 21, 2025
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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
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5'isomiR-183-5p|+2 elicits tumor suppressor activity in a negative feedback loop with E2F1
Xiaoya Li1,2,3, Birgitta Elisabeth Michels1, Oyku Ece Tosun1,4
1Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Summary
This study reveals that different variants of microRNA-183-5p (isomiRs) have distinct roles in triple-negative breast cancer. One specific isomiR, miR-183-5p|+2, inhibits cancer cell proliferation by targeting E2F1, suggesting a regulatory feedback loop.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- MicroRNAs (miRNAs) and their variants (isomiRs) are crucial regulators of gene expression in tumorigenesis.
- 5'isomiRs possess unique seed sequences, leading to altered target specificity and broader phenotypic effects compared to canonical miRNAs.
- The specific functions of most 5'isomiRs remain largely uncharacterized.
Purpose of the Study:
- To investigate the distinct functions of microRNAs (miRNAs) and their 5'isomiRs.
- To explore the role of miR-183-5p and its variants in breast cancer, particularly in triple-negative breast cancer (TNBC).
Main Methods:
- Assessed 5'isomiR expression in The Cancer Genome Atlas (TCGA) breast cancer dataset.
- Investigated phenotypic effects (migration, proliferation, tumor growth, metastasis) of miR-183 overexpression in TNBC cell lines in vitro and in vivo.
- Validated direct targeting of E2F1 by miR-183-5p|+2 using a 3'UTR luciferase assay.
Main Results:
- Three variants of miR-183-5p (miR-183-5p|0, miR-183-5p|+1, miR-183-5p|+2) were highly expressed in TCGA breast cancer data.
- Overexpression of pre-miR-183 reduced proliferation and invasion in TNBC cell lines; miR-183-5p|+2 specifically inhibited proliferation and cell cycle progression.
- miR-183-5p|+2 directly targets E2F1, reducing E2F target gene expression and potentially forming a negative feedback loop with E2F1-mediated regulation of miR-183-5p expression.
Conclusions:
- 5'isomiRs derived from the same pre-miRNA can possess distinct functions, collectively influencing phenotypes.
- miR-183-5p|+2 counteracts pre-miRNA expression by downregulating the transcriptional activator E2F1.
- This regulatory axis may serve as a mechanism to prevent uncontrolled cell proliferation, a process often dysregulated in cancer.
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