MicroRNA-4476 promotes glioma progression through a miR-4476/APC/β-catenin/c-Jun positive feedback loop

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/β-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/β-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.