Oncotarget

Research Papers:

MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells

Xing Guo, Hao Xue, Xiaofan Guo, Xiao Gao, Shugang Xu, Shaofeng Yan, Xiao Han, Tong Li, Jie Shen and Gang Li _

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Oncotarget. 2015; 6:41620-41637. https://doi.org/10.18632/oncotarget.5871

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Abstract

Xing Guo1, Hao Xue1, Xiaofan Guo1, Xiao Gao1, Shugang Xu3, Shaofeng Yan1, Xiao Han1, Tong Li1, Jie Shen1, Gang Li1,2

1Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China

2Brian Science Research Institute, Shandong University, Jinan, Shandong Province, P.R. China

3Department of Neurosurgery, Dezhou People’s Hospital, Dezhou, Shandong Province, P.R. China

Correspondence to:

Gang Li, e-mail: [email protected]

Jie Shen, e-mail: [email protected]

Keywords: hypoxia, autophagy, microRNAs, autophagy-related genes, glioblastoma

Received: April 29, 2015     Accepted: October 09, 2015     Published: October 19, 2015

ABSTRACT

Human glioblastoma multiforme (GBM) is a malignant solid tumor characterized by severe hypoxia. Autophagy plays a protective role in cancer cells under hypoxia. However, the microRNA (miRNA)-related molecular mechanisms underlying hypoxia-reduced autophagy remain poorly understood in GBM. In this study, we performed a miRNA microarray analysis on GBM cells and found that numerous miRNAs were differentially expressed under hypoxic conditions. Further research showed that miR224-3p, one of the significantly down-regulated miRNAs, was involved in regulating hypoxia-induced autophagy in GBM cells. Overexpression of miR224-3p abolished hypoxia-induced autophagy, whereas knocking down endogenous miR224-3p increased autophagic activity under normoxia. In addition, we demonstrated that miR224-3p inhibited autophagy by directly suppressing the expression of two autophagy-related genes (ATGs), ATG5 and FAK family-interacting protein of 200 kDa (FIP200). Furthermore, in vitro, miR224-3p attenuated cell proliferation and promoted hypoxia-induced apoptosis, and in vivo, overexpression of miR224-3p inhibited tumorigenesis of GBM cells. Collectively, our study identified a novel hypoxia-down-regulated miRNA, miR224-3p, as a key modulator of autophagy by inhibiting ATGs in GBM cells.


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