Hsa_circ_0001361 promotes bladder cancer invasion and metastasis through miR-491-5p/MMP9 axis
Hsa_circ_0001361 promotes bladder cancer invasion and metastasis through miR-491-5p/MMP9 axis
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Hsa_circ_0001361通过miR-491-5p/MMP9轴促进膀胱癌侵袭和转移
DOI：
10.1038/s41388-019-1092-z
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Jiang, Guosong
中科院分区：
文献类型：
--
作者：
Liu, Feng;Zhang, Hui;Jiang, Guosong
越来越多的研究表明，环状RNA（CircRNA）在多种恶性肿瘤的发生、发展过程中起着重要的作用。我们先前的研究通过高通量测序发现数百种circRNA在膀胱癌（BC）中异常表达，并且我们已经证实下调的circRNA circHIPK 3、circRNA BCRC-3和circNR 3C 1在BC进展中起抑制作用。在本研究中，我们专注于上调的circRNA，并确定了一个新的环状RNA，hsa_circ_0001361（circ 0001361），在BC组织和细胞系中高水平表达，基于RNA-Seq数据和qRT-PCR分析，它与病理分级和肌肉浸润呈正相关。此外，Kaplan-Meier生存分析提示，circ 0001361高表达水平的BC患者的总体生存率较差。在功能上，circ 0001361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。从机制上讲，RNA测序分析表明，MMP 9在circ 0001361过表达的BC细胞中上调，MMP 9被证实介导circ 0001361诱导的细胞迁移和侵袭。此外，我们证明了circ 0001361可以直接与miR-491- 5 p相互作用以上调MMP 9表达。综上所述，我们的研究结果表明circ 0001361通过靶向miR-491- 5 p/MMP 9轴在BC侵袭和转移中发挥致癌作用，可能成为BC治疗的潜在新靶点。
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.