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Background <p>Olaparib resistance is an inevitable clinical challenge for ovarian cancer treatment, and the heterogeneity of drug resistance requires the development of more potential targets to collaboratively overcome the resistance. The present study aimed to uncover the role of circular RNA (circRNA) involved in olaparib resistance.</p> Methods <p>UWB1.289 (UWB) and PEO1 cells carrying BRCA1/2 mutation were induced to establish olaparib-resistant cells (UWB-OR and PEO1-OR). Whole-transcriptome analysis was performed to identify differentially expressed circRNAs (DECs) and genes (DEGs) in the resistant cell lines. Candidate DEG and DEC were screened using bioinformatics analysis, circRNA-miRNA-mRNA regulatory network, and quantitative polymerase chain reaction. The malignant biological behavior of cells was assessed using cell biological function assays. A dual-luciferase reporter assay was conducted to evaluate the binding ability between RNAs.</p> Results <p>The resistant cells exhibited enhanced proliferation, colony-forming and DNA repair abilities in the condition supplemented with olaparib. Ninety-seven DECs and 190 DEGs were screened in resistant cell lines. The ceRNA network covered four upregulated DEGs and eight upregulated DECs. circRNA14781 and nerve growth factor receptor (NGFR) levels were both upregulated, and miR-330-5p levels decreased in UWB-OR and PEO1-OR. Overexpression of circRNA14781 promoted olaparib resistance and enhanced colony-forming and migratory abilities of UWB and PEO1 cells, which were then reversed by co-overexpression of miR-330-5p. Knockdown of circRNA14781 enhanced the sensitivity to olaparib and weakened the resistant phenotype of UWB-OR and PEO1-OR cells, and the simultaneous inhibition of miR-330-5p offset these changes. miR-330-5p could bind with circRNA14781 and NGFR in vitro. Co-overexpression of NGFR in resistant cells restored the drug-resistance, proliferation, colony-forming, migratory, and DNA repair abilities weakened by miR-330-5p overexpression. Furthermore, knockdown of NGFR enhanced the drug-sensitivity, and suppressed these abilities of the resistant cells.</p> Conclusion <p>circRNA14781 promoted olaparib resistance in ovarian cancer cells by sponging miR-330-5p and upregulating NGFR. circRNA14781 and NGFR could be the potential targets to overcome olaparib resistance in ovarian cancer.</p>

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CircRNA14781 promotes olaparib resistance of ovarian cancer cells by regulating miR-330-5p/NGFR pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Benjun Chen,
  • Shi Zong,
  • Junying Tang,
  • Hongmei Wang,
  • Xiaojing Lu,
  • Jianwei Wang,
  • Xiaochao Jia

摘要

Background

Olaparib resistance is an inevitable clinical challenge for ovarian cancer treatment, and the heterogeneity of drug resistance requires the development of more potential targets to collaboratively overcome the resistance. The present study aimed to uncover the role of circular RNA (circRNA) involved in olaparib resistance.

Methods

UWB1.289 (UWB) and PEO1 cells carrying BRCA1/2 mutation were induced to establish olaparib-resistant cells (UWB-OR and PEO1-OR). Whole-transcriptome analysis was performed to identify differentially expressed circRNAs (DECs) and genes (DEGs) in the resistant cell lines. Candidate DEG and DEC were screened using bioinformatics analysis, circRNA-miRNA-mRNA regulatory network, and quantitative polymerase chain reaction. The malignant biological behavior of cells was assessed using cell biological function assays. A dual-luciferase reporter assay was conducted to evaluate the binding ability between RNAs.

Results

The resistant cells exhibited enhanced proliferation, colony-forming and DNA repair abilities in the condition supplemented with olaparib. Ninety-seven DECs and 190 DEGs were screened in resistant cell lines. The ceRNA network covered four upregulated DEGs and eight upregulated DECs. circRNA14781 and nerve growth factor receptor (NGFR) levels were both upregulated, and miR-330-5p levels decreased in UWB-OR and PEO1-OR. Overexpression of circRNA14781 promoted olaparib resistance and enhanced colony-forming and migratory abilities of UWB and PEO1 cells, which were then reversed by co-overexpression of miR-330-5p. Knockdown of circRNA14781 enhanced the sensitivity to olaparib and weakened the resistant phenotype of UWB-OR and PEO1-OR cells, and the simultaneous inhibition of miR-330-5p offset these changes. miR-330-5p could bind with circRNA14781 and NGFR in vitro. Co-overexpression of NGFR in resistant cells restored the drug-resistance, proliferation, colony-forming, migratory, and DNA repair abilities weakened by miR-330-5p overexpression. Furthermore, knockdown of NGFR enhanced the drug-sensitivity, and suppressed these abilities of the resistant cells.

Conclusion

circRNA14781 promoted olaparib resistance in ovarian cancer cells by sponging miR-330-5p and upregulating NGFR. circRNA14781 and NGFR could be the potential targets to overcome olaparib resistance in ovarian cancer.