Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, China.
Department of Urology, Huashan Hospital, Fudan University, Urumuqi Road No. 12, Shanghai, 200040, China.
J Exp Clin Cancer Res. 2021 Feb 22;40(1):76. doi: 10.1186/s13046-021-01864-3.
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.
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.
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.
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.
越来越多的证据表明，环状 RNA（circRNAs）作为新型非编码 RNA，在癌症发生和肿瘤进展中发挥着关键作用。然而，circRNAs 在透明细胞肾细胞癌（ccRCC）中的功能和分子机制在很大程度上仍是未知的。
在临床样本、ccRCC 细胞和体内动物模型中鉴定了 circAGAP1 的表达和功能。通过荧光原位杂交、RNA 免疫沉淀和荧光素酶报告基因实验研究了 circAGAP1 的分子机制。
与相邻非肿瘤组织相比，ccRCC 组织中 circAGAP1 的表达显著上调。此外，circAGAP1 的表达与患者 ccRCC 的肿瘤大小、核分级和临床分期密切相关。机制研究表明，细胞质 circAGAP1 在 RNA 诱导的沉默复合物中靶向 miR-15-5p。此外，miR-15-5p 在 ccRCC 中表达下调。荧光素酶报告基因实验表明，E2F 转录因子 3（E2F3）是 miR-15-5p 的靶基因，并且在 ccRCC 中上调的 E2F3 表达与 circAGAP1 呈正相关。此外，体外和体内实验表明，circAGAP1 的促肿瘤功能可以通过 miR-15-5p 模拟物来缓解。
我们的研究结果表明，circAGAP1 通过海绵吸附 miR-15-5p 发挥其致癌功能作为竞争性内源性 RNA（ceRNA），从而促进 E2F3 的表达。靶向 circAGAP1 可能是 ccRCC 治疗的一种新的有吸引力的策略。
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