Hypoxia-driven miR-1307-3p promotes hepatocellular carcinoma cell proliferation and invasion by modulating DAB2 interacting protein

Hypoxia is a common feature of the solid tumor microenvironment that is presented as poor clinical outcomes in multiple tumor types, including HCC. Hypoxia stabilizes HIF-1 alpha/HIF-2 alpha, which then moves into the nucleus and binds with HIF-1 beta to form a transcription complex, thereby promoting the transcription of target genes, including mRNAs, miRNAs and lncRNAs to exert their biological functions. Here, through a series of functional assay, including hypoxia culture, MTT, colony-formation, Transwell, qRT-PCR and western blot, we confirmed that miR-1307-3p, as a novel hypoxia-responsive factor, can be directly transcribed by HIF-1 alpha rather than HIF-2 alpha. Hypoxia-driven miR-1307-3p facilitated proliferation and invasion of HCC cells via repressing DAB2IP. More-over, under hypoxia microenvironment, DAB2IP, as a direct target of miR-1307-3p, was down-regulated to activate AKT/mTOR signaling to further maintain the expression level of HIF-1 alpha, thereby forming a feedback loop between HIF-1 alpha/miR-1307-3p and DAB2IP. Targeting miR-1307-3p/DAB2IP axis also modulated tumor growth and metastasis in vivo. In summary, there exists a feedback loop between HIF-1 alpha/miR-1307-3p and DAB2IP in HCC. Targeting a vicious feedback loop between HIF-1 alpha/miR-1307-3p and DAB2IP may be a promising strategy to combat HCC.