Qi Lv1, Gangmin Wang2, Yinan Zhang3, Aijun Shen1, Junjun Tang1, Yi Sun4, Chunhui Ma5, Peijun Wang6. 1. Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China. 2. Department of Urology, Huashan Hospital, Fudan University, Urumuqi Road No. 12, Shanghai, 200040, China. 3. Department of Urology, Shandong Provincial Hospital affiliated with Shandong University, Jingwuweiqi Road No. 324, Jinan, 250021, Shandong, China. 4. Department of Urology, No.971 Hospital of the PLA Navy, Qingdao, 266071, Shandong, China. 5. Department of Orthopedics, Shanghai General Hospital of Shanghai Jiaotong University, Wujin Road No. 85, Shanghai, 200080, China. drmachunhui@163.com. 6. Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China. 05810@tongji.edu.cn.
Abstract
BACKGROUND: Accumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown. METHODS: The expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays. RESULTS: circAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo. CONCLUSION: Our results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC.
BACKGROUND: Accumulating evidence has revealed that circular RNAs (circRNAs), as novel noncoding RNAs, play critical roles in carcinogenesis and tumor progression. However, the functions and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) are largely unknown. METHODS: The expression and functions of circAGAP1 were identified in clinical samples, ccRCC cells and in vivo animal models. The molecular mechanism of circAGAP1 was investigated by fluorescence in situ hybridization, RNA immunoprecipitation and luciferase assays. RESULTS: circAGAP1 (circ0058792) expression was significantly upregulated in ccRCC tissues compared to adjacent nontumor tissues. Moreover, the expression of circAGAP1 was closely related to the tumor size, nuclear grade and clinical stage of ccRCC in patients. Mechanistic studies demonstrated that cytoplasmic circAGAP1 targeted miR-15-5p in an RNA-induced silencing complex. Additionally, miR-15-5p expression was downregulated in ccRCC. Luciferase reporter assays showed that E2F transcription factor 3 (E2F3) was a target of miR-15-5p, and upregulated E2F3 expression was positively correlated with circAGAP1 in ccRCC. Furthermore, the tumor-promoting functions of circAGAP1 could be alleviated by miR-15-5p mimics in vitro and in vivo. CONCLUSION: Our results clarify that circAGAP1 exerts its oncogenic functions as a competitive endogenous RNA (ceRNA) by sponging miR-15-5p, which promotes E2F3 expression. Targeting circAGAP1 might be a new attractive therapeutic strategy in ccRCC.
Authors: Srinivas Chava; C Patrick Reynolds; Anup S Pathania; Santhi Gorantla; Larisa Y Poluektova; Don W Coulter; Subash C Gupta; Manoj K Pandey; Kishore B Challagundla Journal: Mol Oncol Date: 2019-11-29 Impact factor: 6.603