Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, No 37 Guoxue Alley, 610041, Chengdu, Sichuan, China.
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Rd, Shanghai, 200032, China.
Cell Death Dis. 2021 Nov 13;12(11):1081. doi: 10.1038/s41419-021-04366-4.
Circular RNA (circRNA), a closed continuous loop formed by back-splicing, has been confirmed to be implicated in a variety of human diseases including cancers. However, the underlying molecular mechanism of circRNA regulating the progression of renal cell carcinoma (RCC) remains largely unclear. In the present study, we identified a novel circular RNA, circESRP1, that derived from the ESRP1 gene locus at 8q22.1 exons. Lower expression of circESRP1 was found in clear cell RCC (ccRCC) tissues and cell lines. Besides, circESRP1 expression level showed inversely correlated with the advanced tumor size, TNM stage and distant metastasis of ccRCC. The expression level of circESRP1 exhibited a positive correlation with CTCF protein but negatively correlated with miR-3942 in 79 ccRCC tissues. In vivo experiments, we found that overexpression of circESRP1 effectively repressed xenograft tumor growth and inhibited c-Myc-mediated EMT progression. CircESRP1 acted as a sponge to competitively bind with miR-3942 as confirmed through RNA pull-down, RIP and dual-luciferase reporter assays. Moreover, CTCF, a downstream target of miR-3942, was validated to specifically promote the circESRP1 transcript expression and regulated by circESRP1/miR-3942 pathway to form a positive feedback loop. We also revealed that the circESRP1/miR-3942/CTCF feedback loop regulated the ccRCC cell functions via c-Myc mediated EMT process. This study provides a novel regulatory model of circRNA via forming a positive-feedback loop that perpetuates the circESRP1/miR-3942/CTCF axis, suggesting that this signaling may serve as a novel target for the treatment of ccRCC.
环状 RNA（circRNA）是一种通过反向剪接形成的闭合连续环，已被证实与多种人类疾病有关，包括癌症。然而，circRNA 调节肾细胞癌（RCC）进展的潜在分子机制在很大程度上仍不清楚。在本研究中，我们鉴定了一种新型环状 RNA，circESRP1，它来源于 8q22.1 外显子上的 ESRP1 基因座。在透明细胞 RCC（ccRCC）组织和细胞系中发现 circESRP1 的表达较低。此外，circESRP1 的表达水平与 ccRCC 的晚期肿瘤大小、TNM 分期和远处转移呈负相关。circESRP1 的表达水平与 CTCF 蛋白呈正相关，与 79 例 ccRCC 组织中的 miR-3942 呈负相关。在体内实验中，我们发现过表达 circESRP1 可有效抑制异种移植肿瘤的生长，并抑制 c-Myc 介导的 EMT 进展。circESRP1 作为一种海绵，通过 RNA 下拉、RIP 和双荧光素酶报告基因测定证实可与 miR-3942 竞争结合。此外，miR-3942 的下游靶点 CTCF 被验证为特异性促进 circESRP1 转录表达，并受 circESRP1/miR-3942 通路调节，形成正反馈环。我们还揭示了 circESRP1/miR-3942/CTCF 正反馈环通过 c-Myc 介导的 EMT 过程调节 ccRCC 细胞功能。本研究提供了一种通过形成正反馈环来调节环状 RNA 的新调控模型，该模型使 circESRP1/miR-3942/CTCF 轴得以维持，提示该信号通路可能成为治疗 ccRCC 的新靶点。
