Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266013, China.
Oncogene. 2020 Feb;39(8):1696-1709. doi: 10.1038/s41388-019-1092-z. Epub 2019 Nov 8.
Circular RNAs (circRNAs) have been increasingly indicated to be important participants in the development and progression of various malignant tumors. Our previous studies found that hundreds of circRNAs were aberrantly expressed in bladder cancer (BC) by high-throughput sequencing and we have confirmed that the downregulated circRNAs circHIPK3, circRNA BCRC-3, and circNR3C1 played inhibitory roles in BC progression. In this study, we focused on the upregulated circRNAs and identified a novel circular RNA, hsa_circ_0001361 (circ0001361), was expressed at high levels in BC tissues and cell lines based on RNA-Seq data and qRT-PCR analysis, and it was positively corelated with pathologic grade and muscle invasion. Moreover, Kaplan-Meier survival analysis implied that BC patients with high circ0001361 expression level had a poor overall survival. Functionally, circ0001361 promoted BC cell invasion and metastasis both in vitro and in vivo, but had no effect on cell cycle and proliferation. Mechanistically, RNA sequencing analysis indicated that MMP9 was upregulated in circ0001361-overexpressed BC cells, and MMP9 was verified to mediate circ0001361-induced cell migration and invasion. Furthermore, we demonstrated that circ0001361 could directly interact with miR-491-5p to upregulate MMP9 expression. Collectively, our findings indicate that circ0001361 plays oncogenic role in BC invasion and metastasis through targeting the miR-491-5p/MMP9 axis, and it might be a potential novel target for BC therapy.
环状 RNA（circRNAs）被越来越多地证明是各种恶性肿瘤发生和发展的重要参与者。我们之前的研究通过高通量测序发现，膀胱癌（BC）中有数百个 circRNAs 表达异常，我们已经证实下调的 circRNAs circHIPK3、circRNA BCRC-3 和 circNR3C1 在 BC 进展中发挥抑制作用。在这项研究中，我们专注于上调的 circRNAs，并根据 RNA-Seq 数据和 qRT-PCR 分析确定了一个新型环状 RNA，hsa_circ_0001361（circ0001361），在 BC 组织和细胞系中表达水平较高，并且与病理分级和肌肉浸润呈正相关。此外，Kaplan-Meier 生存分析表明，BC 患者中高 circ0001361 表达水平的总生存率较差。功能上，circ0001361 在体外和体内均促进 BC 细胞的侵袭和转移，但对细胞周期和增殖没有影响。机制上，RNA 测序分析表明，circ0001361 过表达的 BC 细胞中 MMP9 上调，并且 MMP9 被证实介导了 circ0001361 诱导的细胞迁移和侵袭。此外，我们证明 circ0001361 可以直接与 miR-491-5p 相互作用，上调 MMP9 表达。总之，我们的研究结果表明，circ0001361 通过靶向 miR-491-5p/MMP9 轴在 BC 的侵袭和转移中发挥致癌作用，并且它可能是 BC 治疗的一个潜在的新靶点。
