MicroRNA-940 Targets INPP4A or GSK3β and Activates the Wnt/β-Catenin Pathway to Regulate the Malignant Behavior of Bladder Cancer Cells.
MicroRNA-940 Targets INPP4A or GSK3β and Activates the Wnt/β-Catenin Pathway to Regulate the Malignant Behavior of Bladder Cancer Cells.
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DOI：
10.3727/096504017x14902261600566
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发表时间：
2018-01-19
影响因子：
3.1
通讯作者：
Chen W
中科院分区：
文献类型：
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作者：
Wang R;Wu Y;Huang W;Chen W
本研究旨在探讨microRNA-940（miR-940）在膀胱癌发生发展中的作用及其调控机制。检测miR-940在膀胱癌组织和细胞中的表达。然后将miR-940模拟物、针对INPP 4A（si-INPP 4A）和GSK 3 β（si-GSK 3 β）的miR-940抑制剂小干扰RNA及其相应对照转染到细胞中。我们研究了miR-940、INPP 4A或GSK 3 β对细胞增殖、迁移、侵袭和凋亡的影响。此外，进行靶标预测和荧光素酶报告基因测定以研究miR-940的靶标。还研究了miR-940与Wnt/β-catenin通路之间的调节关系。miR-940在膀胱癌组织和细胞中上调。过表达miR-940可显著增加膀胱癌细胞增殖，促进细胞迁移和侵袭，抑制细胞凋亡。INPP 4A和GSK 3 β是miR-940的直接靶点，敲低INPP 4A或GSK 3 β可显著增加癌细胞的增殖、迁移和侵袭，并抑制细胞凋亡。miR-940过表达后，c-Myc、cyclin D1和β-catenin蛋白表达水平显著升高，p27和p-β-catenin蛋白表达水平显著降低。在抑制miR-940后获得了相反的效果。Tankyrase 1抑制剂XAV 939可抑制Wnt/β-catenin信号通路，显著逆转miR-940过表达对细胞迁移和侵袭的影响。我们的研究结果表明，miR-940的过表达可能通过靶向INPP 4A或GSK 3 β并激活Wnt/β-catenin通路，促进膀胱癌细胞的增殖、迁移和侵袭，并抑制细胞凋亡。我们的发现暗示了抑制miRNA-940在膀胱癌治疗中的关键作用。
In this report, we aimed to explore the role and regulatory mechanism of microRNA-940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. miR-940 mimics, miR-940 inhibitor small interference RNA against INPP4A (si-INPP4A), and GSK3β (si-GSK3β) and their corresponding controls were then transfected into cells. We investigated the effects of miR-940, INPP4A, or GSK3β on cell proliferation, migration, invasion, and apoptosis. Additionally, target prediction and luciferase reporter assays were performed to investigate the targets of miR-940. The regulatory relationship between miR-940 and the Wnt/β-catenin pathway was also investigated. miR-940 was upregulated in bladder cancer tissues and cells. Overexpression of miR-940 significantly increased bladder cancer cell proliferation, promoted migration and invasion, and inhibited cell apoptosis. INPP4A and GSK3β were the direct targets of miR-940, and knockdown of INPP4A or GSK3β significantly increased cancer cell proliferation, migration, and invasion and inhibited cell apoptosis. After miR-940 overexpression, the protein expression levels of c-Myc, cyclin D1, and β-catenin were significantly increased, and the expression levels of p27 and p-β-catenin were markedly decreased. The opposite effects were obtained after suppression of miR-940. XAV939, a tankyrase 1 inhibitor that could inhibit Wnt/β-catenin signaling, significantly reversed the effects of miR-940 overexpression on cell migration and invasion. Our results indicate that overexpression of miR-940 may promote bladder cancer cell proliferation, migration, and invasion and inhibit cell apoptosis via targeting INPP4A or GSK3β and activating the Wnt/β-catenin pathway. Our findings imply the key roles of suppressing miRNA-940 in the therapy of bladder cancer.