Hypoxia-inducible miR-182 enhances HIF1? signaling via targeting PHD2 and FIH1 in prostate cancer.

ABSTRACT: Activation of hypoxia-inducible factor 1? (HIF1?) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1? at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1? level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1? expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1? protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1? were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1? could result in a sustained activation of HIF1? pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.

SUBMITTER: Li Y 

PROVIDER: S-EPMC4513346 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature