Mu Fang, Huang Jiaxin, Xing Tianyu, Jing Yang, Cui Tingting, Guo Yaqi, Yan Xiaohong, Li Hui, Wang Ning
Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin, China.
Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China.
Front Genet. 2019 May 29;10:525. doi: 10.3389/fgene.2019.00525. eCollection 2019.
The miR-17-92 cluster is involved in animal development and homeostasis, and its dysregulation leads to human diseases such as cancer. In the present study, we investigated the functional link between miR-17-92 cluster and Wnt/β-catenin signaling pathway in ICP2 and DF1 cells. We demonstrated that ectopic expression of either LEF1 or β-catenin increased the promoter activity of the miR-17-92 cluster host gene (MIR17HG) and combined ectopic expression of LEF1 and β-catenin further enhanced the promoter activity; while knockdown of either LEF1 or β-catenin reduced the MIR17HG promoter activity. Both LEF1 and β-catenin could directly bind to the MIR17HG promoter. Furthermore, we demonstrated that low doses of lithium chloride (LiCl), an activator of Wnt/β-catenin signaling pathway, increased MIR17HG promoter activity and the endogenous expression of the miR-17-92 cluster, while high doses of LiCl had the opposite effects. Treatment with XAV-939, an inactivator of the Wnt/β-catenin pathway, reduced the endogenous expression of miR-17-92 cluster. Finally, we found that low doses of LiCl promoted the proliferation of ICP2 and DF1 cells, while high doses of LiCl inhibited the proliferation of ICP2 and DF1 cells. Taken together, our results reveal that MIR17HG is a target of LEF1 and the Wnt/β-catenin pathway and suggest that the miR-17-92 cluster may, at least in part, mediate the proliferation-promoting effect of the Wnt/β-catenin pathway in cell proliferation.
miR-17-92簇参与动物发育和体内平衡，其失调会导致癌症等人类疾病。在本研究中，我们研究了ICP2和DF1细胞中miR-17-92簇与Wnt/β-连环蛋白信号通路之间的功能联系。我们证明，LEF1或β-连环蛋白的异位表达增加了miR-17-92簇宿主基因（MIR17HG）的启动子活性，LEF1和β-连环蛋白的联合异位表达进一步增强了启动子活性；而敲低LEF1或β-连环蛋白则降低了MIR17HG启动子活性。LEF1和β-连环蛋白都可以直接结合到MIR17HG启动子上。此外，我们证明，低剂量的氯化锂（LiCl），一种Wnt/β-连环蛋白信号通路的激活剂，增加了MIR17HG启动子活性和miR-17-92簇的内源性表达，而高剂量的LiCl则有相反的作用。用Wnt/β-连环蛋白通路的失活剂XAV-939处理可降低miR-17-92簇的内源性表达。最后，我们发现低剂量的LiCl促进了ICP2和DF1细胞的增殖，而高剂量的LiCl抑制了ICP2和DF1细胞的增殖。综上所述，我们的结果表明MIR17HG是LEF1和Wnt/β-连环蛋白通路的靶点，并提示miR-17-92簇可能至少部分介导了Wnt/β-连环蛋白通路在细胞增殖中的促增殖作用。
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