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 d...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.展开更多
基金supported by Shanghai Natural Science Foundation(Grant Number 22ZR1456600)Science and Technology Innovation Action Plan in Shanghai on Experimental Animal Research(Grant Number 22140903600)+1 种基金Clinical Research and Cultivation Project of Tongji Hospital in Shanghai(Grant Number ITJ(QN)2201)the National Natural Science Foundation of China(Nos.82227807,81830059)。
文摘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.
