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A Synthetic Sponge System Against miRNAs of the miR-17/92 Cluster Targets Transcriptional MYC Dosage Compensation in

Diana M Bravo-Estupiñan1,2,3,4,5, Carsten Geiß6, Jorge L Arias-Arias2

  • 1Programa de Doctorado en Ciencias, Sistema de Estudios de Posgrado (SEP), Universidad de Costa Rica, San José 20601, Costa Rica.

Cells
|September 13, 2025
PubMed
Abstract

Insights

Targeting microRNAs (miRNAs) with synthetic sponges disrupts MYC gene dosage compensation in cancer. This approach selectively induces cell death in MYC-amplified cancer cells, offering a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic instability drives cancer progression via copy number variations and disrupted gene dosage.
  • The MYC oncogene is frequently affected by copy number variations, with overexpression tightly regulated to prevent cytotoxicity.
  • MicroRNAs (miRNAs) from the miR-17/92 cluster mediate gene dosage compensation for MYC in aneuploid cancer cells.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting miRNA-mediated MYC dosage compensation.
  • To design and validate synthetic miRNA sponges targeting key miRNAs in the miR-17/92 cluster.
  • To assess the impact of disrupting MYC dosage compensation on cancer cell viability.

Main Methods:

  • Design and validation of synthetic miRNA sponges targeting miR-17, miR-19a, and miR-20a.
  • Utilizing breast cancer MCF7 cells with stable MYC overexpression to evaluate sponge constructs.
  • Quantitative RT-PCR to measure miRNA and MYC expression levels.
  • Functional assays in colorectal cancer cell lines to assess cell death induction.

Main Results:

  • Synthetic miRNA sponges significantly reduced miR-17/92 cluster miRNA expression.
  • Sponge treatment led to a corresponding increase in endogenous MYC levels.
  • Transfection with miRNA sponges induced a time-dependent increase in cancer cell death.
  • Cytotoxicity correlated positively with MYC copy number, indicating gene dosage sensitivity.

Conclusions:

  • Synthetic miRNA sponges effectively disrupt MYC dosage compensation by targeting the miR-17/92 cluster.
  • This disruption leads to selective cytotoxicity in cancer cells with MYC amplification.
  • Targeting miRNA-mediated compensation represents a viable therapeutic strategy for MYC-amplified cancers.
Keywords:
MYCaneuploidycancer gene therapygene dosage compensationgenomic instabilitymiR-17/92 clustermiRNA inhibitionmicroRNA spongesynthetic biologytumor suppressor regulation

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