Related Experiment Video

Updated: May 26, 2026

Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
09:40

Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer

Published on: August 2, 2024

The miR-221-5p/RAD18/RAD51 Axis Regulates DNA Damage Tolerance and Homologous Recombination to Drive Platinum

Tasmin Rahman Omy, Naresh Sah, Subash Kairamkonda

    Biorxiv : the Preprint Server for Biology
    |May 25, 2026
    PubMed

    Insights

    Loss of miR-221-5p promotes ovarian cancer chemoresistance by increasing DNA damage repair proteins RAD18 and RAD51. Restoring miR-221-5p re-sensitizes ovarian cancer to platinum drugs and PARP inhibitors.

    Area of Science:

    • Oncology
    • Epigenetics
    • Molecular Biology

    Background:

    • Platinum resistance is a major challenge in ovarian cancer (OC) treatment.
    • Hyperactivation of DNA damage response (DDR) pathways contributes to chemoresistance.
    • Epigenetic mechanisms driving chemoresistance in OC are not fully understood.

    Purpose of the Study:

    • To identify novel post-transcriptional regulatory mechanisms in OC chemoresistance.
    • To investigate the role of miR-221-5p in regulating DDR effectors RAD18 and RAD51.
    • To explore the therapeutic potential of targeting the miR-221-5p/RAD18/RAD51 axis.

    Main Methods:

    • Bioinformatic analysis and luciferase reporter assays to confirm direct targeting of RAD18 and RAD51 by miR-221-5p.
    • Analysis of OC clinical specimens and cell lines to correlate miR-221-5p expression with RAD18/RAD51 levels.
    • Functional assays assessing the impact of miR-221-5p restoration on DNA damage tolerance, homologous recombination, and chemosensitivity.
    • In vivo xenograft models to evaluate the anti-tumor efficacy of stable miR-221-5p expression.

    Main Results:

    • miR-221-5p directly targets the 3'UTRs of RAD18 and RAD51.
    • Downregulation of miR-221-5p inversely correlates with RAD18/RAD51 expression in OC.
    • Restoration of miR-221-5p suppressed platinum-induced DNA repair (PCNA mono-ubiquitination and HR), inducing "functional BRCAness".
    • miR-221-5p re-sensitized OC cells to carboplatin and PARP inhibition.
    • In vivo studies showed stable miR-221-5p expression significantly reduced tumor burden.

    Conclusions:

    • Loss of tumor suppressor miR-221-5p drives ovarian cancer chemoresistance by upregulating RAD18 and RAD51.
    • The miR-221-5p/RAD18/RAD51 axis represents a novel regulatory mechanism in OC chemoresistance.
    • Targeting this axis offers a promising therapeutic strategy for overcoming platinum resistance in ovarian cancer.

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