Dataset Information

HIF1?/miR-199a/ADM feedback loop modulates the proliferation of human dermal microvascular endothelial cells (HDMECs) under hypoxic condition.

ABSTRACT: Hypoxia-inducible factor 1? (HIF1?) plays a protective role in the hypoxia-induced cellular injury. In the present study, we attempted to investigate the role and mechanism of HIF1?in human dermal microvascular endothelial cells (hDMECs), a common-used cell model for researches on the hypoxia-induced injury during skin wounds healing. As revealed by ChIP and online tools prediction and confirmed by luciferase reporter and ChIP assays, HIF1A can bind to the promoter regions of ADM and miR-199a, while miR-199a directly binds to the 3'UTR of HIF1A and ADM. Hypoxia stress induces HIF1? and ADM expression while inhibits miR-199a expression. Under hypoxic condition, HIF1? knockdown increases the nucleus translocation of p65 and the release of TNF-? and IL-8, inhibits the proliferation and migration, while promotes the cellular permeability in HDMECs upon hypoxic stress, while ADM overexpression and miR-199a inhibition exerted an opposite effect on HDMECs. ADM overexpression or miR-199a inhibition could partially reverse the effect of HIF1A knockdown under hypoxia. In summary, we demonstrate a feedback loop consists of HIF1?, miR-199a, and ADM which protect HDMECs from hypoxia-induced cellular injury by modulating the inflammation response, cell proliferation, migration and permeability in HDMECs.

SUBMITTER: Sun Y

PROVIDER: S-EPMC6791693 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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HIF1α/miR-199a/ADM feedback loop modulates the proliferation of human dermal microvascular endothelial cells (HDMECs) under hypoxic condition.

Sun Yang Y Xiong Xiang X Wang Xiancheng X

Cell cycle (Georgetown, Tex.) 20190919 21

Hypoxia-inducible factor 1α (HIF1α) plays a protective role in the hypoxia-induced cellular injury. In the present study, we attempted to investigate the role and mechanism of HIF1αin human dermal microvascular endothelial cells (hDMECs), a common-used cell model for researches on the hypoxia-induced injury during skin wounds healing. As revealed by ChIP and online tools prediction and confirmed by luciferase reporter and ChIP assays, HIF1A can bind to the promoter regions of <i>ADM</i> and miR- ...[more]

PMID: 31537150

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Project description:ObjectiveThe statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.MethodsDeregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry.ResultsHigh HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.ConclusionOur study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

Dataset Information

HIF1?/miR-199a/ADM feedback loop modulates the proliferation of human dermal microvascular endothelial cells (HDMECs) under hypoxic condition.

Publications

HIF1α/miR-199a/ADM feedback loop modulates the proliferation of human dermal microvascular endothelial cells (HDMECs) under hypoxic condition.

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