Role of miR-96/EVI1/miR-449a Axis in the Nasopharyngeal Carcinoma Cell Migration and Tumor Sphere Formation
Role of miR-96/EVI1/miR-449a Axis in the Nasopharyngeal Carcinoma Cell Migration and Tumor Sphere Formation
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DOI：
10.3390/ijms21155495
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发表时间：
2020-08-01
影响因子：
5.6
通讯作者：
Mak, Nai-Ki
中科院分区：
文献类型：
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作者：
Chan, Lai-Sheung;Lung, Hong-Lok;Mak, Nai-Ki
Wnt信号通路是肿瘤干细胞（cancer stem cells， CSC）的主要信号通路之一。生态亲和性病毒整合位点1 （Ecotropic Viral Integration Site 1, EVI1）最近被证明通过与包括Wnt信号通路在内的多种信号通路相互作用来调节肿瘤细胞的致癌发展。本研究发现Wnt调节剂ICG-001可抑制鼻咽癌细胞中EVI1的表达。功能缺失和功能获得的研究结果显示，EVI1的表达对NPC细胞迁移和csc富集肿瘤球的生长均有正向调节作用。随后的研究表明，ICG-001通过上调miR-96的表达抑制EVI1的表达。EVI1 3 ' UTR荧光素酶报告基因检测结果证实EVI1是miR-96的直接靶点。进一步的机制研究表明，ICG-001、过表达miR-96或敲低EVI1表达可恢复miR-449a的表达。在鼻咽癌细胞中证实了miR-449a对细胞迁移和肿瘤球形成的抑制作用。综上所述，miR-96/EVI1/miR-449a轴是参与icg -001介导的鼻咽癌细胞迁移和肿瘤球生长抑制的新途径。
The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres. Subsequent studies indicated ICG-001 inhibited EVI1 expression via upregulated expression of miR-96. Results from EVI1 3 ' UTR luciferase reporter assay confirmed that EVI1 is a direct target of miR-96. Further mechanistic studies revealed that ICG-001, overexpression of miR-96, or knockdown of EVI1 expression could restore the expression of miR-449a. The suppressive effect of miR-449a on the cell migration and tumor sphere formation was confirmed in NPC cells. Taken together, the miR-96/EVI1/miR-449a axis is a novel pathway involved in ICG-001-mediated inhibition of NPC cell migration and growth of the tumor spheres.