bims-hypoxi 2021-05-09 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021‒05‒09
twelve papers selected by
Ashish Kaul
University of Tsukuba

Short exposure to intermittent hypoxia increases erythropoietin levels in healthy individuals.
HIF-1α is necessary for activation and tumour-promotion effect of cancer-associated fibroblasts in lung cancer.
Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis.
Surgically Induced Ischemia has no Impact on Protein Expression Levels of HIF-1α and Related Biomarkers in Renal Cell Carcinoma.
Temporal Quantitative Proteomics Reveals Proteomic and Phosphoproteomic Alterations Associated with Adaptive Response to Hypoxia in Melanoma Cells.
Upregulation of Nogo-B by HIF-1 and AP-1 in hepatocellular carcinoma.
[Roxadustat (Evrenzo® tablet), a therapeutic drug for renal anemia: pharmacological characteristics and clinical evidence in Japan].
The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy.
Hypoxia-inducible factor-1α-mediated upregulation of CD99 promotes the proliferation of placental mesenchymal stem cells by regulating ERK1/2.
MiR-939-5p suppresses PM2.5-induced endothelial injury via targeting HIF-1α in HAECs.
The effect of chronic intermittent hypoxia on atherosclerosis in rat offspring.
Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases.

J Appl Physiol (1985). 2021 May 06.

Short exposure to intermittent hypoxia increases erythropoietin levels in healthy individuals.

Frank Wojan, Sten Stray-Gundersen, Mercedes J Nagel, Sophie Lalande.

  Few minutes of hypoxic exposure stabilizes hypoxia-inducible factor-1α, resulting in erythropoietin (EPO) gene transcription and production. The objective of this study was to identify the shortest intermittent hypoxia protocol necessary to increase serum EPO levels in healthy individuals. In a first experiment, spontaneous EPO changes under normoxia (NORM) and the EPO response to five 4-minute cycles of intermittent hypoxia (IH5) were determined in six individuals. In a second experiment, the EPO response to eight 4-minute cycles of intermittent hypoxia (IH8) and 120 minutes of continuous hypoxia (CONT) was determined in six individuals. All hypoxic protocols were performed at a targeted arterial oxygen saturation of 80%. There was no significant change in EPO levels in response to normoxia or in response to five cycles of intermittent hypoxia (NORM: 9.5±1.8 to 10.5±1.8, IH5: 11.4±2.3 to 13.4±2.1 mU/ml, main effect for time p=0.35). There was an increase in EPO levels in response to eight cycles of intermittent hypoxia and 120 minutes of continuous hypoxia, with peak levels observed 4.5 hours after the onset of hypoxia (IH8: 11.2±2.0 to 16.7±2.2, CONT: 11.1±3.8 to 19.4±3.8 mU/ml, main effect for time p˂0.01). Eight cycles of intermittent hypoxia increased EPO levels to a similar extent as 120 minutes of continuous hypoxia (main effect for condition p=0.36). Intermittent hypoxia did not affect blood pressure. Eight 4-minute cycles of intermittent hypoxia represent the shortest protocol to increase serum EPO levels in healthy individuals.

Keywords:  continuous; erythropoietin; healthy individuals; hypoxia; intermittent

DOI:  https://doi.org/10.1152/japplphysiol.00941.2020
J Cell Mol Med. 2021 May 04.

HIF-1α is necessary for activation and tumour-promotion effect of cancer-associated fibroblasts in lung cancer.

Yana Zhang, Yangyang Bian, Yuan Wang, Yuanyuan Wang, Xixi Duan, Yuning Han, Lijing Zhang, Fei Wang, Zhuoyu Gu, Zhihai Qin.

  Cancer-associated fibroblasts (CAFs) activation is crucial for the establishment of a tumour promoting microenvironment, but our understanding of CAFs activation is still limited. In this study, we found that hypoxia-inducible factor-1α (HIF-1α) was highly expressed in CAFs of human lung cancer tissues and mouse spontaneous lung tumour. Accordingly, enhancing the expression of HIF-1α in fibroblasts via hypoxia induced the conversion of normal fibroblasts into CAFs. HIF-1α-specific inhibitor or HIF-1α knockout (KO) significantly attenuated CAFs activation, which was manifested by the decreased expression of COL1A2 and α-SMA. In vivo, during tumour formation, the expression of Ki-67 and proliferating cell nuclear antigen (PCNA) in the tumour tissue with HIF-1α KO fibroblasts was significantly lower than that of normal fibroblasts. Moreover, HIF-1α in fibroblasts could activate the NF-κB signalling pathway and enhance a subsequent secretion of CCL5, thus promoting the tumour growth. In conclusion, our results suggest that HIF-1α is essential for the activation and tumour-promotion function of CAFs in lung cancer (LC). And targeting HIF-1α expression on CAFs may be a promising strategy for LC therapy.

Keywords:  CAFs; CCL5; HIF-1α; fibroblasts; lung cancer

DOI:  https://doi.org/10.1111/jcmm.16556
Proc Natl Acad Sci U S A. 2021 May 11. pii: e2020490118. [Epub ahead of print]118(19):

Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis.

Ru Wang, Ines Godet, Yongkang Yang, Shaima Salman, Haiquan Lu, Yajing Lyu, Qiaozhu Zuo, Yufeng Wang, Yayun Zhu, Chelsey Chen, Jianjun He, Daniele M Gilkes, Gregg L Semenza.

  Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

Keywords:  cell motility; invasion; metastasis; migration; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2020490118
APMIS. 2021 May 04.

Surgically Induced Ischemia has no Impact on Protein Expression Levels of HIF-1α and Related Biomarkers in Renal Cell Carcinoma.

M L Mikkelsen, N Marcussen, M Rabjerg.

  BACKGROUND AND PURPOSE: The increasing demands for personalized targeted therapy directed against Renal Cell Carcinoma has driven a search for predictive markers. Novel therapies targeting HIF-1α in Renal Cell Carcinoma have been developed and HIF-1α has been suggested as a novel predictive marker of response to therapy. The surgical resection of a kidney tumor induces tissue ischemia and HIF-1α is an oxygen-sensitive transcription factor, which is known to be up-regulated during hypoxia.MATERIALS AND METHODS: This study investigated the impact of intra-surgical and post-surgical ischemia on protein expression levels of HIF-1α and three related biomarkers (VEGF, GLUT-1 and CAIX) in 20 patients with Renal Cell Carcinoma with immunohistochemistry and Western Blotting.
RESULTS: Surgical ischemia did not have a significant impact on protein expression levels of any of the investigated markers. Long post-surgical ischemia resulted in reduced expression levels of HIF-1α, probably due to autolysis.
INTERPRETATION: Our results suggest that HIF-1α is a stable protein, with expression levels not affected by intra-surgical ischemia and hence HIF-1α is suited for marker analysis.

Keywords:  hypoxia; hypoxia-inducible factor 1α; predictive marker; prognostic marker

DOI:  https://doi.org/10.1111/apm.13131
Cancers (Basel). 2021 Apr 30. pii: 2175. [Epub ahead of print]13(9):

Temporal Quantitative Proteomics Reveals Proteomic and Phosphoproteomic Alterations Associated with Adaptive Response to Hypoxia in Melanoma Cells.

Keshava K Datta, Parthiban Periasamy, Sonali V Mohan, Rebekah Ziegman, Harsha Gowda.

  Hypoxia is a common feature in various solid tumours, including melanoma. Cancer cells in hypoxic environments are resistant to both chemotherapy and radiation. Hypoxia is also associated with immune suppression. Identification of proteins and pathways that regulate cancer cell survival in hypoxic environments can reveal potential vulnerabilities that can be exploited to improve the efficacy of anticancer therapies. We carried out temporal proteomic and phosphoproteomic profiling in melanoma cell lines to identify hypoxia-induced protein expression and phosphorylation changes. By employing a TMT-based quantitative proteomics strategy, we report the identification and quantitation of >7000 proteins and >10,000 phosphosites in melanoma cell lines grown in hypoxia. Proteomics data show metabolic reprogramming as one of the prominent adaptive responses in hypoxia. We identify several novel hypoxia-mediated phosphorylation changes that have not been reported before. They reveal kinase signalling pathways that are potentially involved in modulating cellular response to hypoxia. In addition to known protein expression changes, we identify several novel proteomic alterations associated with adaptive response to hypoxia. We show that cancer cells require the ubiquitin-proteasome system to survive in both normoxia and hypoxia. Inhibition of proteasome activity affects cell survival and may provide a novel therapeutic avenue to target cancer cells in hypoxia. Our study can serve as a valuable resource to pursue novel candidates to target hypoxia in cancers and improve the efficacy of anticancer therapies.

Keywords:  kinome; mass spectrometry; phosphoproteome; proteasome; proteome

DOI:  https://doi.org/10.3390/cancers13092175
Cancer Sci. 2021 May 08.

Upregulation of Nogo-B by HIF-1 and AP-1 in hepatocellular carcinoma.

Dingding Han, Penggao Yang, Bo Qin, Guoqing Ji, Yanhua Wu, Long Yu, Hong Zhang.

  Nogo-B is an important regulator of tumor angiogenesis. Expression of Nogo-B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo-B in liver cancer. In response to hypoxia, expression of Nogo-B significantly increased in HCC tissues and cells. The distal hypoxia-responsive element (HRE) in the promoter was essential for transcriptional activation of Nogo-B under hypoxic conditions, which is the specific site for HIF-1α binding. In addition, Nogo-B expression was associated with c-Fos expression in HCC tissues. Nogo-B expression was induced by c-Fos, yet inhibited by a dominant negative mutant A-Fos. Deletion and mutation analysis of the predicted AP-1 binding sites revealed that functional element mediated the induction of Nogo-B promoter activity, which was confirmed by chromatin immunoprecipitation. These results indicate that HIF-1α and c-Fos induce the expression of Nogo-B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo-B in tumor angiogenesis.

Keywords:  HIF-1α; Nogo-B; c-Fos; hepatocellular carcinoma; hypoxia

DOI:  https://doi.org/10.1111/cas.14941
Nihon Yakurigaku Zasshi. 2021 ;156(3): 187-197

[Roxadustat (Evrenzo® tablet), a therapeutic drug for renal anemia: pharmacological characteristics and clinical evidence in Japan].

Tohru Ugawa, Mizue Ashizaki, Asami Murata, Yoshikatsu Majikawa.

Roxadustat (Evrenzo® tablet) is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. Roxadustat has been approved for the treatment of renal anemia in patients on dialysis in September 2019 in Japan. By inhibiting HIF-PH, roxadustat suppresses the degradation of HIF-α, a subunit of the heterodimeric transcription factor HIF, leading to its accumulation and activation of the HIF pathway. Similar to activation of the HIF pathway in response to hypoxia, the production of endogenous erythropoietin is increased and erythropoiesis is stimulated. Moreover, roxadustat stimulates erythropoiesis efficiently by improving iron bioavailability. The efficacy and mechanism of action of roxadustat have been detailed in non-clinical pharmacology studies. Rat models of anemia demonstrated efficacy of roxadustat in correcting anemia and changes in gene expression leading to increased iron bioavailability. Four phase 3 clinical studies in Japan clearly demonstrated the efficacy of roxadustat in patients with renal anemia on dialysis. Roxadustat showed an acceptable safety profile, and the incidences and types of adverse events and serious adverse events reported in the clinical studies were similar with those predicted to occur in these patient population. Since roxadustat is an oral drug, concerns present with erythropoiesis-stimulating agents (ESAs) such as the risk of infection to the medical staff due to accidental needle-stick, pain during ESA injection in patients and burden on patients to visit a hospital, can be avoided or reduced. In November 2020, roxadustat has also been approved for the treatment of renal anemia in patients not on dialysis (data not shown in this article).

DOI: https://doi.org/10.1254/fpj.21001
Front Pharmacol. 2021 ;12 636892

The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy.

Yue Li, Long Zhao, Xiao-Feng Li.

  Hypoxia is an important feature of most solid tumors, conferring resistance to radiation and many forms of chemotherapy. However, it is possible to exploit the presence of tumor hypoxia with hypoxia-activated prodrugs (HAPs), agents that in low oxygen conditions undergo bioreduction to yield cytotoxic metabolites. Although many such agents have been developed, we will focus here on TH-302. TH-302 has been extensively studied, and we discuss its mechanism of action, as well as its efficacy in preclinical and clinical studies, with the aim of identifying future research directions.

Keywords:  Chemotherapy; Hypoxia; Hypoxia-activated prodrugs; TH-302; radiotherapy

DOI:  https://doi.org/10.3389/fphar.2021.636892
World J Stem Cells. 2021 Apr 26. 13(4): 317-330

Hypoxia-inducible factor-1α-mediated upregulation of CD99 promotes the proliferation of placental mesenchymal stem cells by regulating ERK1/2.

Xu-Dong Feng, Jia-Qi Zhu, Jia-Hang Zhou, Fei-Yan Lin, Bing Feng, Xiao-Wei Shi, Qiao-Ling Pan, Jiong Yu, Lan-Juan Li, Hong-Cui Cao.

  BACKGROUND: As human placenta-derived mesenchymal stem cells (hP-MSCs) exist in a physiologically hypoxic microenvironment, various studies have focused on the influence of hypoxia. However, the underlying mechanisms remain to be further explored.AIM: The aim was to reveal the possible mechanisms by which hypoxia enhances the proliferation of hP-MSCs.
METHODS: A hypoxic cell incubator (2.5% O2) was used to mimic a hypoxic microenvironment. Cell counting kit-8 and 5-ethynyl-20-deoxyuridine incorporation assays were used to assay the proliferation of hP-MSCs. The cell cycle was profiled by flow cytometry. Transcriptome profiling of hP-MSCs under hypoxia was performed by RNA sequencing. CD99 mRNA expression was assayed by reverse transcription-polymerase chain reaction. Small interfering RNA-mediated hypoxia-inducible factor 1α (HIF-1α) or CD99 knockdown of hP-MSCs, luciferase reporter assays, and the ERK1/2 signaling inhibitor PD98059 were used in the mechanistic analysis. Protein expression was assayed by western blotting; immunofluorescence assays were conducted to evaluate changes in expression levels.
RESULTS: Hypoxia enhanced hP-MSC proliferation, increased the expression of cyclin E1, cyclin-dependent kinase 2, and cyclin A2, and decreased the expression of p21. Under hypoxia, CD99 expression was increased by HIF-1α. CD99-specific small interfering RNA or the ERK1/2 signaling inhibitor PD98059 abrogated the hypoxia-induced increase in cell proliferation.
CONCLUSION: Hypoxia promoted hP-MSCs proliferation in a manner dependent on CD99 regulation of the MAPK/ERK signaling pathway in vitro.

Keywords:  CD99; Hypoxia; Hypoxia-inducible factor 1α; MAPK/ERK signaling pathway; Mesenchymal stem cells; Proliferation; RNA sequencing assay

DOI:  https://doi.org/10.4252/wjsc.v13.i4.317
Nanotoxicology. 2021 May 03. 1-15

MiR-939-5p suppresses PM2.5-induced endothelial injury via targeting HIF-1α in HAECs.

Shuang Liang, Ruihong Ning, Jingyi Zhang, Jiangyan Liu, Jie Zhang, Heqing Shen, Rui Chen, Junchao Duan, Zhiwei Sun.

  Ambient air pollution is a leading cause of non-communicable disease in the world. PM2.5 has the potential to change the miRNAs profiles, which in turn causes cardiovascular effects. Hypoxia-inducible factor (HIF)-1 plays a critical role in the development of atherosclerosis. Yet, the possible role of miR-939-5p/HIF-1α in PM2.5-induced endothelial injury remains elusive. Therefore, the study aims to investigate the effects of miR-939-5p and HIF-1α on PM2.5-triggered endothelial injury. The results from immunofluorescence, qRT-PCR, LSCM, and western blot assays demonstrated that PM2.5 increased the levels of HIF-1α, inflammation and apoptosis in human aortic endothelial cells (HAECs). Yet, the inflammatory response and mitochondrial-mediated apoptosis pathway were effectively inhibited in HIF-1α knockdown HAECs lines. The expression of miR-939-5p was significantly down-regulated in HAECs after exposed to PM2.5. The luciferase reporter, qRT-PCR and western blot results demonstrated that miR-939-5p could directly targeted HIF-1α. And the miR-939-5p overexpression restricted PM2.5-triggered decreases in cell viability and increases in lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and inflammation. In addition, miR-939-5p overexpression remarkably suppressed PM2.5-triggered BcL-2/Bax ratio reduction and Cytochrome C, Cleaved Caspase-9 and Cleaved Caspase-3 expression increase, revealed that miR-939-5p hampered PM2.5-induced endothelial apoptosis through mitochondrial-mediated apoptosis pathway. Our results demonstrated that PM2.5 increased the expression of HIF-1α followed by a pro-inflammatory and apoptotic response in HAECs. The protective effect of miR-939-5p on PM2.5-triggered endothelial cell injury by negatively regulating HIF-1α. miR-939-5p might present a new therapeutic target for PM2.5 induced endothelial injury.

Keywords:  HAECs; PM2.5; endothelial injury; hypoxia-inducible factor; miR-939-5p

DOI:  https://doi.org/10.1080/17435390.2021.1917716
Int J Cardiol. 2021 May 03. pii: S0167-5273(21)00808-1. [Epub ahead of print]

The effect of chronic intermittent hypoxia on atherosclerosis in rat offspring.

Ziyan Wang, Yiming Zeng, Huihuang Lin.

  BACKGROUND: To determine whether rat offspring born under conditions of chronic intermittent hypoxia (CIH) would develop systemic inflammation and be susceptible to CIH-mediated injury on artery.METHODS: CIH rat model was established. The expression levels of p38MAPK, NF-κB p65, CRP, TNFα, and IL-8 were measured. The arterial pathology of offspring whose mothers were exposed to CIH during pregnancy was evaluated.
RESULTS: The levels of p-P38MAPK and NF-κB p65 were significantly up-regulated following induction of intra-uterine CIH Induction of intra- and extra-uterine CIH had an interaction regarding the expression profiles of these markers (P < 0.01, P < 0.01, P < 0.01, P < 0.01, P = 0.020, respectively). Pathologic analysis of the arteries confirmed that intra-uterine CIH increased the tunica intima thickness (P < 0.01), but had no effect on the tunica media (P = 0.974). Furthermore, induction of intra- and extra-uterine CIH had a synergistic interaction on tunica intima thickness (P = 0.004).
CONCLUSIONS: Intra-uterine CIH caused tunica intima thickening and development of pre-atherosclerotic lesions in offspring via NF-κB p65 and p-p38 MAPK. Furthermore, the expression of NF-κB p65 and p-p38 MAPK and the extent of pre-atherosclerotic lesions were either exacerbated or alleviated in offspring when re-exposed to CIH later.

Keywords:  Atherosclerosis; Chronic intermittent hypoxia; Inflammation; Offspring; Sleep apnea

DOI:  https://doi.org/10.1016/j.ijcard.2021.04.065
J Cell Mol Med. 2021 May 04.

Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases.

Cunyao Pan, Zhaoli Chen, Chao Li, Tie Han, Hui Liu, Xinxing Wang.

  Sestrin2 (SESN2) is a conserved stress-inducible protein (also known as hypoxia-inducible gene 95 (HI95)) that is induced under hypoxic conditions. SESN2 represses the production of reactive oxygen species (ROS) and provides cytoprotection against various noxious stimuli, including hypoxia, oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. In recent years, the determination of the regulation and signalling mechanisms of SESN2 has increased our understanding of its role in the hypoxic response. SESN2 has well-documented roles in hypoxia-related diseases, making it a potential target for diagnosis and treatment. This review discusses the regulatory mechanisms of SESN2 and highlights the significance of SESN2 as a biomarker and therapeutic target in hypoxia-related diseases, such as cancer, respiratory-related diseases, cardiovascular diseases and cerebrovascular diseases.

Keywords:  cytoprotection; hypoxia; regulatory mechanism; sestrin2; therapeutic target

DOI:  https://doi.org/10.1111/jcmm.16540