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Published on: April 25, 2022
MicroRNAs of miR-17-92 cluster increase gene expression by targeting mRNA-destabilization pathways
Eunsun Jung1, Youngmo Seong2, Bohyun Jeon1
1Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
Abstract:
MicroRNAs (miRNAs) of the miR-17-92 cluster are overexpressed in human cancers, and their enforced expression is tumorigenic in mouse models. A number of genes are reported to be targets of these miRNAs and are implicated in their tumorigenic potential. However, the mode of action by miRNAs suggests that global analysis of their targets is required to understand their cellular roles. In this study, we globally analyzed AGO2-bound mRNAs and found that the miR-17-92 miRNAs coherently repress multiple targets involved in the destabilization of mRNA. While the miRNAs repress the expression of their targets, they increase stability and lengthen the poly-A tails of non-target mRNAs. Furthermore, the expression of BTG3, TOB1, CSNK1A1 and ANKRD52 is negatively correlated with the expression of the miR-17-92 cluster in cancer cell lines. Our results suggest that the miR-17-92 miRNAs promote tumorigenesis not only by repression of key regulators, but also by posttranscriptional increases of global gene expression.
Insights
The miR-17-92 microRNAs (miRNAs) promote cancer by repressing mRNA destabilization targets and increasing global gene expression stability. This dual action contributes to tumorigenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Regulation
Background:
- MicroRNAs (miRNAs) of the miR-17-92 cluster are frequently overexpressed in human cancers.
- Their enforced expression has been shown to be tumorigenic in mouse models.
- Understanding the global targets and mechanisms of these miRNAs is crucial for elucidating their cellular roles in cancer.
Purpose of the Study:
- To globally analyze the messenger RNA (mRNA) targets of the miR-17-92 microRNAs.
- To investigate the impact of miR-17-92 on mRNA stability and polyadenylation.
- To explore the correlation between miR-17-92 expression and specific gene expression in cancer cell lines.
Main Methods:
- Global analysis of Argonaute 2 (AGO2)-bound mRNAs to identify miRNA targets.
- Assessment of mRNA stability and poly-A tail length.
- Correlation analysis of miR-17-92 cluster expression with target genes (BTG3, TOB1, CSNK1A1, ANKRD52) in cancer cell lines.
Main Results:
- The miR-17-92 miRNAs coherently repress multiple mRNA targets involved in mRNA destabilization.
- These miRNAs increase the stability and lengthen the poly-A tails of non-target mRNAs.
- Expression of BTG3, TOB1, CSNK1A1, and ANKRD52 is negatively correlated with miR-17-92 cluster expression in cancer cell lines.
Conclusions:
- The miR-17-92 miRNAs contribute to tumorigenesis through a dual mechanism.
- They repress key regulatory targets involved in mRNA destabilization.
- They also promote tumorigenesis by increasing global gene expression posttranscriptionally, enhancing mRNA stability.
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