Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway
Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway
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环状RNA MYLK作为竞争性内源RNA通过调节VEGFA/VEGFR2信号通路促进膀胱癌进展
DOI：
10.1016/j.canlet.2017.06.027
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发表时间：
2017-09-10
期刊：
影响因子：
9.7
通讯作者：
Chen, Junxia
中科院分区：
文献类型：
--
作者：
Zhong, Zhenyu;Huang, Mengge;Chen, Junxia
越来越多的证据表明，环状RNA（circRNA）在调节基因表达中发挥着至关重要的作用。然而，circRNA 背后的机制在很大程度上仍然难以捉摸。在这里，我们使用微阵列分析筛选了膀胱癌 (BC) 的 circRNA 和 mRNA 表达谱。我们发现 circRNA-MYLK 和 VEGFA 在 BC 中显着上调并共表达。重要的是，circRNA-MYLK 水平与 BC 的分期和分级进展相关。从机制上讲，我们证明了 circRNA-MYLK 可以直接与 miR-29a 结合并减轻对靶标 VEGFA 的抑制，从而激活 VEGFA/VEGFR2 信号通路。在功能上，我们发现异位表达circRNA-MYLK加速了HUVEC的细胞增殖、迁移、管形成和重新排列的细胞骨架。此外，上调circRNA-MYLK可促进上皮间质转化（EMT）。而 circRNA-MYLK 敲低会降低细胞增殖、运动并诱导细胞凋亡。最后，上调circRNA-MYLK促进BC异种移植物的生长、血管生成和转移。综上所述，本研究首次证明 circRNA-MYLK 可能作为 miR-29a 的竞争性内源 RNA (ceRNA)，通过激活 VEGFA/VEGFR2 和下游 Ras/ERK 信号通路促进 EMT 和 BC 的发展。我们的数据表明 circRNA-MYLK 将成为 BC 诊断和治疗的一个有前景的靶点。 (C) 2017 Elsevier B.V. 保留所有权利。
Accumulating evidences indicate that circular RNAs (circRNAs) play a vital role in modulating gene expression. However, the mechanisms underlying circRNAs remain largely elusive. Here, we screened circRNA and mRNA expression profiles of bladder carcinoma (BC) using microarray analysis. We found that circRNA-MYLK and VEGFA were significantly up-regulated and co-expressed in BC. Importantly, circRNA-MYLK levels were related to the progression of stage and grade of BC. Mechanistically, we demonstrated that circRNA-MYLK could directly bind to miR-29a and relieve suppression for target VEGFA, which activated VEGFA/VEGFR2 signaling pathway. Functionally, we found that ectopically expressing circRNA-MYLK accelerated cell proliferation, migration, tube formation of HUVEC and rearranged cytoskeleton. Moreover, up-regulating circRNA-MYLK promoted epithelial-mesenchymal transition (EMT). Whereas circRNA-MYLK knockdown decreased cell proliferation, motility, and induced apoptosis. Finally, up-regulating circRNA-MYLK promoted the growth, angiogenesis and metastasis of BC xenografts. Taken together, this study demonstrated for the first time that circRNA-MYLK might function as competing endogenous RNA (ceRNA) for miR-29a, which could contribute to EMT and the development of BC through activating VEGFA/VEGFR2 and downstream Ras/ERK signaling pathway. Our data suggest that circRNA-MYLK would be a promising target for BC diagnosis and therapy. (C) 2017 Elsevier B.V. All rights reserved.