Endocrine targets of hypoxia-inducible factors

Lee, Hsiu Chi; Tsai, Shaw-Jenq

doi:10.1530/joe-16-0653

Cited by 15 publications

(11 citation statements)

References 93 publications

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“…Studies have found that necrotic tissue produced by injury has a lower oxygen level than healthy normal tissue [49,54,55]. HIF-2α is restricted to certain tissues [56], and HIF-3α is a negative regulator of HIF [57].…”

Section: Role Of the Hif-1α Signaling Pathway In Heterotopic Ossificationmentioning

confidence: 99%

The hypoxic microenvironment: a driving force for heterotopic ossification progression

2020

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Heterotopic ossification (HO) refers to the formation of bone tissue outside the normal skeletal system. According to its pathogenesis, HO is divided into hereditary HO and acquired HO. There currently lack effective approaches for HO prevention or treatment. A deep understanding of its pathogenesis will provide promising strategies to prevent and treat HO. Studies have shown that the hypoxia-adaptive microenvironment generated after trauma is a potent stimulus of HO. The hypoxic microenvironment enhances the stability of hypoxia-inducible factor-1α (HIF-1α), which regulates a complex network including bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF), and neuropilin-1 (NRP-1), which are implicated in the formation of ectopic bone. In this review, we summarize the current understanding of the triggering role and underlying molecular mechanisms of the hypoxic microenvironment in the initiation and progression of HO, focusing mainly on HIF-1 and it's influenced genes BMP, VEGF, and NRP-1. A better understanding of the role of hypoxia in HO unveils novel therapeutic targets for HO that reduce the local hypoxic microenvironment and inhibit HIF-1α activity.

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Section: Role Of the Hif-1α Signaling Pathway In Heterotopic Ossificationmentioning

confidence: 99%

The hypoxic microenvironment: a driving force for heterotopic ossification progression

2020

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“…Since hypoxia is a master regulator for endometriosis development 4, 14, we tested whether hypoxia is able to inhibit EZH2 expression. Results showed that hypoxia decreased EZH2 expression while increased ANTXR2 expression in the eutopic stromal cell ( Figure 2D-E ).…”

Section: Resultsmentioning

confidence: 99%

Targeting Anthrax Toxin Receptor 2 Ameliorates Endometriosis Progression

Lin¹,

Lee²,

Hsu³

et al. 2019

Theranostics

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Rationale: Endometriosis is a highly prevalent gynecological disease in women of reproductive age that markedly reduces life quality and fertility. Unfortunately, there is no cure for this disease, which highlights that more efforts are needed to investigate the underlying mechanism for designing novel therapeutic regimens. This study aims to investigate druggable membrane receptors distinctively expressed in endometriotic cells. Methods: Bioinformatic analysis of public databases was employed to identify potential druggable candidates. Normal endometrial tissues and ectopic endometriotic lesions were obtained for the determination of target genes. Primary endometrial and endometriotic stromal cells as well as two different mouse models of endometriosis were used to characterize molecular mechanisms and therapeutic outcomes of endometriosis, respectively. Results: Anthrax toxin receptor 2 (ANTXR2) mRNA and protein are upregulated in the endometriotic specimens. Elevation of ANTXR2 promotes endometriotic cell adhesion, proliferation, and angiogenesis. Furthermore, hypoxia is the driving force for ANTXR2 upregulation via altering histone modification of ANTXR2 promoter by reducing the repressive mark, histone H3 lysine 27 (H3K27) trimethylation, and increasing the active mark, H3K4 trimethylation. Activation of ANTXR2 signaling leads to increased Yes-associated protein 1 (YAP1) nuclear translocation and transcriptional activity, which contributes to numerous pathological processes of endometriosis. Pharmacological blocking of ANTXR2 signaling not only prevents endometriotic lesion development but also causes the regression of established lesion. Conclusion: Taken together, we have identified a novel target that contributes to the disease pathogenesis of endometriosis and provided a potential therapeutic regimen to treat it.

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“…Previously, in skeletal muscle cells, PGC-1α was shown to enhance hypoxia-inducing factor (HIF)-1α-dependent gene expression by increasing mitochondrial oxygen consumption (O'Hagan et al, 2009). Interestingly, the HIFbinding site (hypoxia-responsive element) is located in the survivin promoter, and hypoxia has recently been shown to play critical roles in endometriosis development and progression (Lee and Tsai, 2017). Thus, the crosstalk between PGC-1α and apoptotic factors under hypoxia warrants investigation.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ coactivator 1α-mediated pathway as a possible therapeutic target in endometriosis

et al. 2019

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STUDY QUESTION: Is a peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)-mediated pathway involved in the development of endometriosis? SUMMARY ANSWER: PGC-1α plays critical roles in inflammation and cell proliferation of endometriotic tissues and may be involved in the development of endometriosis. WHAT IS KNOWN ALREADY: Expression levels of PGC-1α are higher in ovarian endometrioma (OE) than normal endometrium (NE). PGC-1α also stimulates aromatase activity and promotes local estrogen biosynthesis in OE. STUDY DESIGN, SIZE, DURATION: This is a case-controlled biological study using endometrial cells and tissues derived from 23 women with, and 10 women without, OE. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ectopic endometriotic and eutopic endometrial stromal cells (SCs) were isolated and maintained in culture. PGC-1α was either overexpressed in the cells or knocked down using siRNA. The expression of PGC-1α and other factors during endometriosis was examined using real-time PCR and western blotting, cell proliferation was measured using Cell Counting Kit-8 (WST-8) assays and transcriptional activity was assessed using luciferase reporter assays. MAIN RESULTS AND THE ROLE OF CHANCE: PGC-1α overexpression promoted the proliferation of OESCs in a time-dependent manner (P < 0.01 versus control) but not NESCs. PGC-1α stimulated aromatase (P < 0.01 versus control) and interleukin (IL)-6/IL-8 mRNA expression levels (P < 0.05 versus control for each) and led to inhibitor kappa B phosphorylation protein expression and upregulation of the apoptosis inhibitors X-linked inhibitor of apoptosis protein and survivin at mRNA level (P < 0.05 versus control for each). HX531, a selective retinoid-X receptor-α (RXRα) antagonist, suppressed the PGC-1α-induced cell proliferation (P < 0.05 versus control), aromatase/IL-6/ IL-8/survivin mRNA expression (P < 0.05 versus control for each) and transcription reporter activity of PGC-1α in a dose-dependent manner (P < 0.01 versus control). Moreover, HX531 downregulated PGC-1α-induced aromatase-promoter PI.3-II transcripts in OESCs, and PGC-1α knockdown reduced aromatase, IL-6/IL-8 and antiapoptotic factors mRNA expression (P < 0.05 versus control for each). Notably, the Histogram score, which was used for quantifying RXRα status, was markedly higher in OE than in NE tissue (P < 0.01). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Only OE tissues were included in this study, while peritoneal and deep infiltrating endometriotic tissues were not. Therefore, these findings might not be generalized to other types of endometriosis.

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Endocrine targets of hypoxia-inducible factors

Cited by 15 publications

References 93 publications

The hypoxic microenvironment: a driving force for heterotopic ossification progression

The hypoxic microenvironment: a driving force for heterotopic ossification progression

Targeting Anthrax Toxin Receptor 2 Ameliorates Endometriosis Progression

Peroxisome proliferator-activated receptor-γ coactivator 1α-mediated pathway as a possible therapeutic target in endometriosis

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