Role of microRNA-4739 in enhancing cisplatin chemosensitivity by negative regulation of RHBDD2 in human cervical cancer cells

Role of microRNA-4739 in enhancing cisplatin chemosensitivity by negative regulation of RHBDD2 in human cervical cancer cells

Cisplatin (DDP) is a widely used chemotherapy drug for advanced cervical cancer (CC), but resistance poses a significant challenge. While miR-4739 has been implicated in tumor development, its specific role in regulating DDP resistance in CC remains unclear. We analyzed the expression levels of miR-...

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Bibliographic Details
Published in:Cellular & molecular biology letters Vol. 29; no. 1; pp. 20 - 15
Main Authors: Li, Yuling, Zhou, Zhengtong, Qu, Jinfeng, Gong, Peiling, Wei, Yuyan, Sun, Yaping
Format: Journal Article
Language:English
Published: England BioMed Central 25-01-2024
BMC
Subjects:
Apoptosis
Caspase-3
Cell adhesion & migration
Cervical cancer
Chemotherapy
Cholecystokinin
Cisplatin
Correlation analysis
Drug resistance
E-cadherin
Flow cytometry
Hypotheses
Medical research
MicroRNAs
miR-4739
miRNA
Patients
Polymerase chain reaction
RHBDD2
Transfection
Tumorigenesis
Tumors
St Louis Missouri
United States > US
China
Japan
Drug resistance
RHBDD2
Cervical cancer
Cisplatin
miR-4739
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Summary:Cisplatin (DDP) is a widely used chemotherapy drug for advanced cervical cancer (CC), but resistance poses a significant challenge. While miR-4739 has been implicated in tumor development, its specific role in regulating DDP resistance in CC remains unclear. We analyzed the expression levels of miR-4739 and RHBDD2 in DDP-resistant and DDP-sensitive CC tissues using quantitative real-time polymerase chain reaction (PCR) and assessed their correlation through Spearman's correlation analysis. DDP-resistant CC cell lines (HeLa/DDP and SiHa/DDP) were established by gradually increasing DDP concentrations, followed by transfection with miR-4739 mimics, si-RHBDD2, or a RHBDD2 overexpression vector. A series of functional assays, including CCK-8 assay, colony formation, flow cytometry, and transwell assay were performed. The interaction between miR-4739 and RHBDD2 was confirmed by luciferase reporter assay. We examined the protein levels of RHBDD2, P-gP, MRP1, cleaved caspase-3, and E-cadherin through western blot analysis. Moreover, we generated xenograft tumors by injecting stably transfected HeLa/DDP cells into mice to compare their tumorigenesis capacity. We observed downregulation of miR-4739 and upregulation of RHBDD2 in DDP-resistant CC tissues and cell lines. MiR-4739 was shown to directly bind to RHBDD2 gene sequences to repress RHBDD2 expression in HeLa/DDP and SiHa/DDP cells. Our in vitro and in vivo experiments demonstrated that overexpressing miR-4739 overcame DDP resistance in CC cells by targeting RHBDD2. Furthermore, RHBDD2 overexpression reversed the effects of miR-4739 mimics on drug-resistance-related proteins (P-gP and MRP1) and the expression of cleaved caspase-3 and E-cadherin in HeLa/DDP cells. In summary, our study revealed that miR-4739 can reverse DDP resistance by modulating RHBDD2 in CC cells.
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content type line 23
ISSN:1689-1392
1425-8153
1689-1392
DOI:10.1186/s11658-024-00532-6