Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan road II, Guangzhou, 510080, People's Republic of China.
Department of Emergency, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan road II, Guangzhou, 510080, People's Republic of China.
Mol Cancer. 2021 Jan 20;20(1):19. doi: 10.1186/s12943-021-01314-w.
There is increasing evidence that circular RNAs (circRNAs) have significant regulatory roles in cancer development and progression; however, the expression patterns and biological functions of circRNAs in renal cell carcinoma (RCC) remain largely elusive.
Bioinformatics methods were applied to screen for circRNAs differentially expressed in RCC. Analysis of online circRNAs microarray datasets and our own patient cohort indicated that circSDHC (hsa_circ_0015004) had a potential oncogenic role in RCC. Subsequently, circSDHC expression was measured in RCC tissues and cell lines by qPCR assay, and the prognostic value of circSDHC evaluated. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of circSDHC on RCC proliferation and metastasis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes.
Clinically, high circSDHC expression was correlated with advanced TNM stage and poor survival in patients with RCC. Further, circSDHC promoted tumor cell proliferation and invasion, both in vivo and in vitro. Analysis of the mechanism underlying the effects of circSDHC in RCC demonstrated that it binds competitively to miR-127-3p and prevents its suppression of a downstream gene, CDKN3, and the E2F1 pathway, thereby leading to RCC malignant progression. Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor.
Our data indicates, for the first time, an essential role for the circSDHC/miR-127-3p/CDKN3/E2F1 axis in RCC progression. Thus, circSDHC has potential to be a new therapeutic target in patients with RCC.
越来越多的证据表明，环状 RNA（circRNA）在癌症的发生和发展中具有重要的调节作用；然而，环状 RNA 在肾细胞癌（RCC）中的表达模式和生物学功能仍在很大程度上难以捉摸。
应用生物信息学方法筛选 RCC 中差异表达的环状 RNA。在线环状 RNA 微阵列数据集和我们自己的患者队列分析表明，环状 SDHC（hsa_circ_0015004）在 RCC 中具有潜在的致癌作用。随后，通过 qPCR 检测 RCC 组织和细胞系中 circSDHC 的表达，并评估 circSDHC 的预后价值。进一步进行了一系列体外和体内功能实验，以评估 circSDHC 对 RCC 增殖和转移的影响。采用 RNA 下拉实验、荧光素酶报告基因和荧光原位杂交实验来验证 circSDHC 与 miR-127-3p 及其靶基因之间的相互作用。
临床上，高 circSDHC 表达与 RCC 患者的晚期 TNM 分期和不良生存相关。此外，circSDHC 促进了体内和体外肿瘤细胞的增殖和侵袭。分析 circSDHC 在 RCC 中的作用机制表明，它与 miR-127-3p 竞争结合，阻止其对下游基因 CDKN3 和 E2F1 通路的抑制作用，从而导致 RCC 的恶性进展。此外，circSDHC 的敲低导致 CDKN3 表达降低和 E2F1 通路抑制，而用 miR-127-3p 抑制剂处理可以挽救这一作用。
我们的数据首次表明，circSDHC/miR-127-3p/CDKN3/E2F1 轴在 RCC 进展中起着重要作用。因此，circSDHC 有可能成为 RCC 患者的新治疗靶点。
