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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Hsa_circ_0038737 promotes PARPi resistance in castration-resistant prostate cancer via IGF2BP3-mediated DNPH1 mRNA
Zhongyuan Wang1,2,3, Qintao Ge1,2,3, Aihetaimujiang Anwaier1,2,3
1Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P.R. China.
Background:
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a major challenge to therapeutic efficacy in castration-resistant prostate cancer (CRPC). Although circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, their involvement in PARPi resistance remains largely uncharacterized.
Objective:
This study aims to elucidate the molecular mechanism by which hsa_circ_0038737 modulates PARPi resistance in CRPC through post-transcriptional regulatory pathways.
Methods:
We employed a comprehensive set of in vitro and in vivo approaches, including qRT-PCR, RNA sequencing, RNA-protein pull-down, RNA immunoprecipitation, functional assays, and xenograft/organoid models, to investigate the biological function and mechanistic role of hsa_circ_0038737 in CRPC progression and therapeutic response.
Results:
We identified hsa_circ_0038737 as a nuclear-enriched circRNA significantly upregulated in CRPC, with expression levels correlating with poor prognosis and aggressive clinical features. Mechanistically, hsa_circ_0038737 interacts with RNA-binding protein (RBP) IGF2BP3, enhancing the stability of DNPH1 mRNA, a nucleotide sanitizer critical for DNA repair. The circRNA-RBP-mRNA regulatory axis promotes PARPi resistance by facilitating DNA damage repair capacity. Moreover, we revealed that reverse-complementary Alu elements mediate circRNA biogenesis, with HNRNPDL facilitating this process. Pharmacologic inhibition of DNPH1 effectively restored PARPi sensitivity both in vitro and in vivo.
Conclusion:
Our findings reveal a novel hsa_circ_0038737/IGF2BP3/DNPH1 axis driving PARPi resistance in CRPC, offering promising potential biomarkers and therapeutic targets to overcome resistance and improve treatment outcomes in advanced prostate cancer.
Insights
Circular RNAs (circRNAs) drive poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in castration-resistant prostate cancer (CRPC). The hsa_circ_0038737/IGF2BP3/DNPH1 pathway enhances DNA repair, promoting resistance, but DNPH1 inhibition restores PARPi sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPi) efficacy is limited by resistance in castration-resistant prostate cancer (CRPC).
- Circular RNAs (circRNAs) role in PARPi resistance in CRPC is largely unknown.
Purpose of the Study:
- To investigate the molecular mechanism of hsa_circ_0038737 in mediating PARPi resistance in CRPC.
- To explore the post-transcriptional regulatory pathways involved in this process.
Main Methods:
- Utilized qRT-PCR, RNA sequencing, RNA-protein pull-down, and RNA immunoprecipitation.
- Conducted functional assays, xenograft, and organoid models in vitro and in vivo.
- Investigated the biological function and mechanistic role of hsa_circ_0038737 in CRPC.
Main Results:
- Identified nuclear-enriched hsa_circ_0038737 upregulated in CRPC, correlating with poor prognosis.
- Discovered hsa_circ_0038737 interacts with IGF2BP3 to stabilize DNPH1 mRNA, enhancing DNA repair and PARPi resistance.
- Demonstrated that DNPH1 inhibition restores PARPi sensitivity in vitro and in vivo.
Conclusions:
- A novel hsa_circ_0038737/IGF2BP3/DNPH1 axis drives PARPi resistance in CRPC.
- This axis represents potential biomarkers and therapeutic targets for overcoming PARPi resistance in advanced prostate cancer.
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