CircNUP50 is a novel therapeutic target that promotes cisplatin resistance in ovarian cancer by modulating p53 ubiquitination
© 2024. The Author(s)..
BACKGROUND: Most patients with ovarian cancer (OC) treated with platinum-based chemotherapy have a dismal prognosis owing to drug resistance. However, the regulatory mechanisms of circular RNA (circRNA) and p53 ubiquitination are unknown in platinum-resistant OC. We aimed to identify circRNAs associated with platinum-resistant OC to develop a novel treatment strategy.
METHODS: Platinum-resistant circRNAs were screened through circRNA sequencing and validated using quantitative reverse-transcription PCR in OC cells and tissues. The characteristics of circNUP50 were analysed using Sanger sequencing, oligo (dT) primers, ribonuclease R and fluorescence in situ hybridisation assays. Functional experimental studies were performed in vitro and in vivo. The mechanism underlying circNUP50-mediated P53 ubiquitination was investigated through circRNA pull-down analysis and mass spectrometry, luciferase reporters, RNA binding protein immunoprecipitation, immunofluorescence assays, cycloheximide chase assays, and ubiquitination experiments. Finally, a platinum and si-circNUP50 co-delivery nanosystem (PscDPP) was constructed to treat platinum-resistant OC in an orthotopic animal model.
RESULTS: We found that circNUP50 contributes to platinum-resistant conditions in OC by promoting cell proliferation, affecting the cell cycle, and reducing apoptosis. The si-circNUP50 mRNA sequencing and circRNA pull-down analysis showed that circNUP50 mediates platinum resistance in OC by binding p53 and UBE2T, accelerating p53 ubiquitination. By contrast, miRNA sequencing and circRNA pull-down experiments indicated that circNUP50 could serve as a sponge for miR-197-3p, thereby upregulating G3BP1 to mediate p53 ubiquitination, promoting OC platinum resistance. PscDPP effectively overcame platinum resistance in an OC tumour model and provided a novel idea for treating platinum-resistant OC using si-circNUP50.
CONCLUSIONS: This study reveals a novel molecular mechanism by which circNUP50 mediates platinum resistance in OC by modulating p53 ubiquitination and provides new insights for developing effective therapeutic strategies for platinum resistance in OC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Journal of nanobiotechnology - 22(2024), 1 vom: 19. Jan., Seite 35 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhu, Yunshu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.01.2024 Date Revised 22.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12951-024-02295-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM367337150 |
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| 100 | 1 | |a Zhu, Yunshu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CircNUP50 is a novel therapeutic target that promotes cisplatin resistance in ovarian cancer by modulating p53 ubiquitination |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 22.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: Most patients with ovarian cancer (OC) treated with platinum-based chemotherapy have a dismal prognosis owing to drug resistance. However, the regulatory mechanisms of circular RNA (circRNA) and p53 ubiquitination are unknown in platinum-resistant OC. We aimed to identify circRNAs associated with platinum-resistant OC to develop a novel treatment strategy | ||
| 520 | |a METHODS: Platinum-resistant circRNAs were screened through circRNA sequencing and validated using quantitative reverse-transcription PCR in OC cells and tissues. The characteristics of circNUP50 were analysed using Sanger sequencing, oligo (dT) primers, ribonuclease R and fluorescence in situ hybridisation assays. Functional experimental studies were performed in vitro and in vivo. The mechanism underlying circNUP50-mediated P53 ubiquitination was investigated through circRNA pull-down analysis and mass spectrometry, luciferase reporters, RNA binding protein immunoprecipitation, immunofluorescence assays, cycloheximide chase assays, and ubiquitination experiments. Finally, a platinum and si-circNUP50 co-delivery nanosystem (PscDPP) was constructed to treat platinum-resistant OC in an orthotopic animal model | ||
| 520 | |a RESULTS: We found that circNUP50 contributes to platinum-resistant conditions in OC by promoting cell proliferation, affecting the cell cycle, and reducing apoptosis. The si-circNUP50 mRNA sequencing and circRNA pull-down analysis showed that circNUP50 mediates platinum resistance in OC by binding p53 and UBE2T, accelerating p53 ubiquitination. By contrast, miRNA sequencing and circRNA pull-down experiments indicated that circNUP50 could serve as a sponge for miR-197-3p, thereby upregulating G3BP1 to mediate p53 ubiquitination, promoting OC platinum resistance. PscDPP effectively overcame platinum resistance in an OC tumour model and provided a novel idea for treating platinum-resistant OC using si-circNUP50 | ||
| 520 | |a CONCLUSIONS: This study reveals a novel molecular mechanism by which circNUP50 mediates platinum resistance in OC by modulating p53 ubiquitination and provides new insights for developing effective therapeutic strategies for platinum resistance in OC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Nanodrug delivery | |
| 650 | 4 | |a Ovarian cancer | |
| 650 | 4 | |a Platinum resistance | |
| 650 | 4 | |a circRNA NUP50 | |
| 650 | 4 | |a p53 | |
| 650 | 7 | |a Cisplatin |2 NLM | |
| 650 | 7 | |a Q20Q21Q62J |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a RNA, Circular |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a DNA Helicases |2 NLM | |
| 650 | 7 | |a EC 3.6.4.- |2 NLM | |
| 650 | 7 | |a Poly-ADP-Ribose Binding Proteins |2 NLM | |
| 650 | 7 | |a RNA Helicases |2 NLM | |
| 650 | 7 | |a EC 3.6.4.13 |2 NLM | |
| 650 | 7 | |a RNA Recognition Motif Proteins |2 NLM | |
| 650 | 7 | |a G3BP1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.4.12 |2 NLM | |
| 650 | 7 | |a UBE2T protein, human |2 NLM | |
| 650 | 7 | |a EC 2.3.2.23 |2 NLM | |
| 650 | 7 | |a Ubiquitin-Conjugating Enzymes |2 NLM | |
| 650 | 7 | |a EC 2.3.2.23 |2 NLM | |
| 700 | 1 | |a Liang, Leilei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yuxi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Yihang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Lingying |e verfasserin |4 aut | |
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