MicroRNA-4476 promotes glioma progression through a miR-4476/APC/β-catenin/c-Jun positive feedback loop
MicroRNA-4476 promotes glioma progression through a miR-4476/APC/β-catenin/c-Jun positive feedback loop
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MicroRNA-4476 通过 miR-4476/APC/β-catenin/c-Jun 正反馈环促进神经胶质瘤进展
DOI：
10.1038/s41419-020-2474-4
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发表时间：
2020-04-23
影响因子：
9
通讯作者：
Zhang, Xian
中科院分区：
文献类型：
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作者：
Lin, Jie;Ding, Shengfeng;Zhang, Xian
胶质瘤一直是一个主要的医疗负担；然而，其发生和发展背后的特定分子调控机制仍有待阐明。虽然已知许多miRNAs参与了胶质瘤恶性表型的调控，但miR-4476的作用尚未见报道。在目前的研究中，我们确定miR-4476是一种上调的microRNA，它促进胶质瘤中细胞的增殖、迁移和侵袭。进一步的机制分析表明，结肠腺瘤性息肉病(APC)是Wnt/β-catenin信号通路的负调控因子，是miR-4476的直接靶点，并介导miR-4476在胶质瘤中的致癌作用。C-jun是Wnt/β-catenin信号转导的下游效应因子，它被miR-4476过表达上调。反过来，c-jun通过与其转录起始点(TSS)上游结合，正向调节miR-4476的表达。此外，在我们的临床标本中，miR-4476的升高是一个不良的预后因素，其表达与c-jun的表达呈正相关，而与APC的表达呈负相关。总之，我们的研究表明miR-4476作为肿瘤增强剂，直接靶向APC刺激其自身表达，促进胶质瘤的恶性表型。
Glioma has been a major healthcare burden; however, the specific molecular regulatory mechanism underlying its initiation and progression remains to be elucidated. Although it is known that many miRNAs are involved in the regulation of malignant phenotypes of glioma, the role of miR-4476 has not been reported yet. In the present study, we identify miR-4476 as an upregulated microRNA, which promotes cell proliferation, migration, and invasion in glioma. Further mechanistic analyses indicate that the adenomatous polyposis coli (APC), a negative regulator of the Wnt/beta -catenin signaling pathway, is a direct target of miR-4476 and mediates the oncogenic effects of miR-4476 in glioma. C-Jun, a downstream effector of the Wnt/beta -catenin signaling, is upregulated by miR-4476 overexpression. In turn, c-Jun could positively regulate miR-4476 expression by binding to the upstream of its transcription start site (TSS). Furthermore, in our clinical samples, increased miR-4476 is an unfavorable prognostic factor, and its expression positively correlates with c-Jun expression but negatively correlates with that of APC. In conclusion, our study demonstrates that miR-4476 acts as a tumor enhancer, directly targeting APC to stimulate its own expression and promoting the malignant phenotypes of glioma.