Circular RNA circAGAP1 promotes sunitinib sensitivity in renal cell carcinoma via sponging multiple PDGFR-targeted miRNAs
QI LV1,#, GANGMIN WANG2,#, YI HONG1, TIANYI ZHU1, SHUANG QIN1, SAIFEI SUN1, YUTING WANG1, YAOHUA LIU1, QING ZHANG1, CHUNHUI MA3,*, PEIJUN WANG1,*
1 Imaging Department, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
2 Urology Department, Huashan Hospital, Fudan University, Shanghai, 200040, China
3 Orthopedic Department, Shanghai General Hospital of Shanghai Jiaotong University, Shanghai, 200080, China
* Corresponding Author: CHUNHUI MA. Email: 
; PEIJUN WANG. Email: 
Oncology Research https://doi.org/10.32604/or.2024.047698
Received 14 November 2023; Accepted 09 April 2024; Published online 04 June 2024
Abstract
Background: Sunitinib resistance is a major challenge in advanced renal cell carcinoma (RCC). Clinically, elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is desirable. In previous studies, we found that circAGAP1 expression was significantly upregulated in clear cell RCC (ccRCC) and was strongly associated with poor prognosis. However, the role of circAGAP1 in sunitinib resistance in ccRCC remains unclear.
Methods: We used public databases for bioinformatics analysis to identify the binding targets of circAGAP1. Additionally, the effects of circAGAP1 on the proliferation, clonogenesis, apoptosis, and migration of ccRCC cells were analyzed using quantitative real-time PCR, cell counting kit-8 assays, migration and apoptosis assays, and colony formation assays. Furthermore, RNA immunoprecipitation, dual-luciferase reporter, and fluorescence
in situ hybridization assays were used to explore the molecular mechanism.
Results: In this study, circAGAP1 exhibited higher expression in sunitinib-sensitive ccRCC cells and inhibited the clonogenesis, proliferation, and migration of ccRCC cells after sunitinib treatment. Mechanical studies revealed that circAGAP1 regulated the expression of sunitinib target platelet-derived growth factor receptor by acting as a microRNA sponge that suppresses miR-149-5p, miR-455-5p, and miR-15a-5p simultaneously. Overexpression of these three miRNAs reversed circAGAP1-mediated sunitinib sensitivity in ccRCC.
Conclusions: In summary, our findings indicate that circAGAP1 may serve as a promising biomarker to predict sunitinib sensibility and a therapeutic target in ccRCC.
Graphical Abstract
Keywords
Renal cell carcinoma; Sunitinib resistance; Circular RNA circAGAP1; MiR-149-5p; MiR-455-5p; MiR-15a-5p
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