HIF1a/HIF2a-miR210-3p network promotes glioblastoma proliferation and tumorigenesis through EGFR-PI3K/AKT signaling pathway with a positive feedback

HIF1a promotes glioblastoma cell proliferation and tumorigenesis under hypoxia conditions, leading to poor prognosis; however, none of the targeted therapies of HIF1a for glioblastoma is success nowadays. Therefore, we focused to look for the reason and wondered whether HIF2a contributed GBM growth. We did gene-chip and found that HIF2a contributed to the malignant progression of glioblastoma while blocking of HIF1a. Furthermore, our results revealed knock-out of HIF1a and HIF2a simultaneously improved the chemo-sensitization significantly. Moreover, miR-210-3p induced HIF1a expression but inhibited HIF2a, which meant the existence of regulation of cycle between HIF1a/HIF2a and miR-210-3p. Traditional studies have proved EGF as an upstream gene regulator of HIF1a in hypoxia conditions through EGFR-PI3K/AKT-mTOR signaling pathway. However, in this study, besides the signaling pathways mentioned above, we found the upstream regulators HIF1a and HIF2a also promoted EGF with the binding regions AGGCGTGG and GGGCGTGG. Briefly, in hypoxia microenvironment HIF1a/HIF2a-miR210-3p network promotes malignant progression of glioblastoma through EGFR-PI3K/AKT-mTOR signaling pathway with a positive feedback. Overall design: The control cells without HIF1a and HIF2a interference, HIF1a-ko, HIF2a-ko and HIF1a/HIF2a knock-out simultaneously cells were cultured under hypoxia conditions for 24h and then the cells were collected. The cells were then sent to undergo miRNA-Seq.