The Fourth Affiliated Hospital, and International Institutes of Medicine, Zhejiang University School of Medicine, Jinhua 322000, Zhejiang, China.
Kidney Disease Center, the First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.
Int J Biol Sci. 2022 Jan 24;18(4):1491-1507. doi: 10.7150/ijbs.69351. eCollection 2022.
Clear cell renal cell carcinoma (ccRCC) is a primary kidney cancer with high aggressive phenotype and extremely poor prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) play pivotal roles in the occurrence and development of various human cancers. However, the expression, clinical significance and regulatory role of circRNAs in ccRCC remain largely unclear. Here we report that circDVL1 to be reduced in the serums and tissues from ccRCC patients, and to negatively correlate with ccRCC malignant features. Overexpression of circDVL1 inhibits proliferation, induces G1/S arrest, triggers apoptosis, and reduces migration and invasion in different ccRCC cells . Correspondingly, circDVL1 overexpression suppresses ccRCC tumorigenicity in a mouse xenograft model. Mechanistically, circDVL1 serves as a sponge for oncogenic miR-412-3p, thereby preventing miR-412-3p-mediated repression of its target protocadherin 7 (PCDH7) in ccRCC cells. Collectively, our results demonstrate that circDVL1 exerts tumor-suppressive function during ccRCC progression through circDVL1/miR-412-3p/PCDH7 axis, and suggest that circDVL1 could be a novel diagnostic and prognositc marker and therapeutic target for ccRCC.
透明细胞肾细胞癌 (ccRCC) 是一种原发性肾癌,具有高度侵袭性表型和极差的预后。越来越多的证据表明,环状 RNA (circRNA) 在各种人类癌症的发生和发展中发挥着关键作用。然而,circRNA 在 ccRCC 中的表达、临床意义和调控作用在很大程度上仍不清楚。本研究报告 circDVL1 在 ccRCC 患者的血清和组织中表达降低,并与 ccRCC 的恶性特征呈负相关。circDVL1 的过表达抑制不同 ccRCC 细胞的增殖,诱导 G1/S 期阻滞,触发细胞凋亡,并减少迁移和侵袭。相应地,circDVL1 在小鼠异种移植模型中抑制 ccRCC 的致瘤性。机制上,circDVL1 作为致癌 miR-412-3p 的海绵,从而防止 miR-412-3p 介导的对其靶基因原钙黏蛋白 7 (PCDH7) 的抑制作用在 ccRCC 细胞中。总之,我们的研究结果表明,circDVL1 通过 circDVL1/miR-412-3p/PCDH7 轴在 ccRCC 进展过程中发挥肿瘤抑制功能,并表明 circDVL1 可能成为 ccRCC 的一种新的诊断和预后标志物和治疗靶点。