bims-hypoxi 2021-07-11 papers

bims-hypoxi

Biomed News

on Hypoxia and HIF1-alpha

Issue of 2021–07–11
eleven papers selected by
Ashish Kaul, University of Tsukuba

The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma.
HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling.
HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury.
Regulation of redox signaling in HIF1-dependent tumor angiogenesis.
Hypoxia-induced preadipocyte factor 1 expression in human lung fibroblasts through ERK/PEA3/c-Jun pathway.
17β-oestradiol alleviates endoplasmic reticulum stress injury induced by chronic cerebral hypoperfusion through the Haemoglobin/HIF 1α signalling pathway in ovariectomized rats.
Tumor protein D52 is upregulated in oral squamous carcinoma cells under hypoxia in a hypoxia-inducible-factor-independent manner and is involved in cell death resistance.
Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases.
3D printing of Cu-doped bioactive glass composite scaffolds promotes bone regeneration through activating the HIF-1α and TNF-α pathway of hUVECs.
SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.
Carcinoma associated fibroblasts small extracellular vesicles with low miR-7641 promotes breast cancer stemness and glycolysis by HIF-1α.

Biomed Pharmacother. 2021 Jul 02. pii: S0753-3322(21)00655-7. [Epub ahead of print]141 111873

The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma.

Mohammad Malekan, Mohammad Ali Ebrahimzadeh, Fateme Sheida.

  Adaptation to the loss of O2 is regulated via the activity of hypoxia-inducible factors such as Hypoxia-Inducible Factor-1 (HIF-1). HIF-1 acts as a main transcriptional mediator in the tissue hypoxia response that regulates over 1000 genes related to low oxygen tension. The role of HIF-1α in oncogenic processes includes angiogenesis, tumor metabolism, cell proliferation, and metastasis, which has been examined in various malignancies, such as melanoma. Melanoma is accompanied by a high death rate and a cancer type whose incidence has risen over the last decades. The linkage between O2 loss and melanogenesis had extensively studied over decades. Recent studies revealed that HIF-1α contributes to melanoma progression via different signaling pathways such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/β-catenin, Notch, and NF-κB. Also, various microRNAs (miRs) are known to mediate the HIF-1α role in melanoma. Therefore, HIF-1α offers a diagnostic/prognostic biomarker and a candidate for targeted therapy in melanoma.

Keywords:  Diagnostic/prognostic biomarker; HIF-1α; Hypoxia; Melanoma; Melanoma treatment; Signaling pathways

DOI:  https://doi.org/10.1016/j.biopha.2021.111873
Front Cell Dev Biol. 2021 ;9 671704

HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling.

Peng Cui, Ping Zhang, Lin Yuan, Li Wang, Xin Guo, Guanghui Cui, Yanmin Zhang, Minghua Li, Xiaowei Zhang, Xiaoqiang Li, Yuxin Yin, Zhendong Yu.

  Hypoxia-inducible factor 1α (HIF-1α) plays pivotal roles in maintaining pluripotency, and the developmental potential of pluripotent stem cells (PSCs). However, the mechanisms underlying HIF-1α regulation of neural stem cell (NSC) differentiation of human induced pluripotent stem cells (hiPSCs) remains unclear. In this study, we demonstrated that HIF-1α knockdown significantly inhibits the pluripotency and self-renewal potential of hiPSCs. We further uncovered that the disruption of HIF-1α promotes the NSC differentiation and development potential in vitro and in vivo. Mechanistically, HIF-1α knockdown significantly enhances mitofusin2 (MFN2)-mediated Wnt/β-catenin signaling, and excessive mitochondrial fusion could also promote the NSC differentiation potential of hiPSCs via activating the β-catenin signaling. Additionally, MFN2 significantly reverses the effects of HIF-1α overexpression on the NSC differentiation potential and β-catenin activity of hiPSCs. Furthermore, Wnt/β-catenin signaling inhibition could also reverse the effects of HIF-1α knockdown on the NSC differentiation potential of hiPSCs. This study provided a novel strategy for improving the directed differentiation efficiency of functional NSCs. These findings are important for the development of potential clinical interventions for neurological diseases caused by metabolic disorders.

Keywords:  differentiation; hypoxia-inducible factor 1α; induced pluripotent stem cells; mitofusin2; neural stem cells

DOI:  https://doi.org/10.3389/fcell.2021.671704
Am J Physiol Renal Physiol. 2021 07 06.

HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury.

Zuo-Lin Li, Jia-Ling Ji, Yi Wen, Jingyuan Cao, Naresh Kharbuja, Wei-Jie Ni, Di Yin, Song-Tao Feng, Hong Liu, Lin-Li Lv, Bi-Cheng Liu, Bin Wang.

  Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from post-translational hydroxylation, mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia/reperfusion (I/R)-, unilateral ureteral obstruction (UUO)-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, nuclear factor-κB (NF-κB), which plays a central role in inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only in hypoxic condition, but also in normoxic condition. Moreover, the induced HIF-1α by inflammation protected against the tubular injury in AKI. Thus, our findings not only provide novel insight into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Keywords:  HIF-1α; NF-κB; acute kidney injury; inflammation; transcriptional regulation

DOI:  https://doi.org/10.1152/ajprenal.00119.2021
FEBS J. 2021 Jul 06.

Regulation of redox signaling in HIF1-dependent tumor angiogenesis.

Valeria Manuelli, Chiara Pecorari, Giuseppe Filomeni, Ester Zito.

  Angiogenesis is the process of blood vessel growth. The angiogenic switch consists of new blood vessel formation that, in carcinogenesis, can lead to the transition from a harmless cluster of dormant cells to a large tumorigenic mass with metastatic potential. Hypoxia, i.e. the scarcity of oxygen, is a hallmark of solid tumors to which they adapt by activating hypoxia-inducible factor-1 (HIF-1), a transcription factor triggering de novo angiogenesis. HIF-1 and the angiogenic molecules that are expressed upon its activation are modulated by redox status. Modulations of the redox environment can influence the angiogenesis signaling at different levels, thereby impinging on the angiogenic switch. This review provides a molecular overview of the redox-sensitive steps in angiogenic signaling, the main molecular players involved and their crosstalk with the unfolded protein response (UPR). New classes of inhibitors of these modulators which might act as antiangiogenic drugs in cancer are also discussed.

Keywords:  ER stress; ERO1; HIF-1; UPR; angiogenesis; hypoxia; metastasis

DOI:  https://doi.org/10.1111/febs.16110
Mol Med. 2021 Jul 06. 27(1): 69

Hypoxia-induced preadipocyte factor 1 expression in human lung fibroblasts through ERK/PEA3/c-Jun pathway.

Wun-Hao Cheng, Chia-Ling Chen, Jing-Yun Chen, Chien-Huang Lin, Bing-Chang Chen.

   BACKGROUND: Several studies have reported that hypoxia plays a pathological role in severe asthma and tissue fibrosis. Our previous study showed that hypoxia induces A disintegrin and metalloproteinase 17 (ADAM17) expression in human lung fibroblasts. Moreover, preadipocyte factor 1 (Pref-1) is cleaved by ADAM17, which participates in adipocyte differentiation. Furthermore, Pref-1 overexpression is involved in tissue fibrosis including liver and heart. Extracellular signal-regulated kinase (ERK) could active downstram gene expression through polyoma enhancer activator 3 (PEA3) phosphorylation. Studies have demonstrated that PEA3 and activator protein 1 (AP-1) play crucial roles in lung fibrosis, and the Pref-1 promoter region contains PEA3 and AP-1 binding sites as predicted. However, the roles of ERK, PEA3, and AP-1 in hypoxia-stimulated Pref-1 expression in human lung fibroblasts remain unknown.
METHODS: The protein expression in ovalbumin (OVA)-induced asthmatic mice was performed by immunohistochemistry and immunofluorescence. The protein expression or the mRNA level in human lung fibroblasts (WI-38) was detected by western blot or quantitative PCR. Small interfering (si) RNA was used to knockdown gene expression. The collaboration with PEA3 and c-Jun were determined by coimmunoprecipitation. Translocation of PEA3 from the cytosol to the nucleus was observed by immunocytochemistry. The binding ability of PEA3 and AP-1 to Pref-1 promoter was assessed by chromatin immunoprecipitation.
RESULTS: Pref-1 and hypoxia-inducible factor 1α (HIF-1α) were expressed in the lung sections of OVA-treated mice. Colocalization of PEA3 and Fibronectin was detected in lung sections from OVA-treated mice. Futhermore, Hypoxia induced Pref-1 protein upregulation and mRNA expression in human lung fibroblasts (WI-38 cells). In 60 confluent WI-38 cells, hypoxia up-regulated HIF-1α and Pref-1 protein expression. Moreover, PEA3 small interfering (si) RNA decreased the expression of hypoxia-induced Pref-1 in WI-38 cells. Hypoxia induced PEA3 phosphorylation, translocation of PEA3 from the cytosol to the nucleus, PEA3 recruitment and AP-1 binding to the Pref-1 promoter region, and PEA3-luciferase activity. Additionally, hypoxia induced c-Jun-PEA3 complex formation. U0126 (an ERK inhibitor), curcumin (an AP-1 inhibitor) or c-Jun siRNA downregulated hypoxia-induced Pref-1 expression.
CONCLUSIONS: These results implied that ERK, PEA3, and AP-1 participate in hypoxia-induced Pref-1 expression in human lung fibroblasts.

Keywords:  AP-1; ERK; Human lung fibroblasts; Hypoxia; PEA3; Pref-1

DOI:  https://doi.org/10.1186/s10020-021-00336-w
Neurochem Int. 2021 Jul 02. pii: S0197-0186(21)00165-0. [Epub ahead of print]148 105119

17β-oestradiol alleviates endoplasmic reticulum stress injury induced by chronic cerebral hypoperfusion through the Haemoglobin/HIF 1α signalling pathway in ovariectomized rats.

Chao Xu, Yongxin Dai, Jing Bai, Bo Ren, Jing Xu, Fujia Gao, Lu Wang, Wenli Zhang, Ruimin Wang.

  Endoplasmic reticulum stress (ERS) is known to be an essential target in protecting against ischaemic brain injury. In this study, using a vascular dementia (VaD) animal model induced by bilateral common carotid artery occlusion (BCCAO), we evaluated the effect and mechanism of 17β-oestradiol (E2) against VaD by inhibiting ERS at the early stage (14 d, 21 d, 28 d) and late stage (3 m) after BCCAO in the hippocampal CA1 region of ovariectomized rats. The results showed that the activation of the PERK-eIF2α-ATF4-CHOP axis, a typical ERS pathway, was significantly increased at the early and late stages after BCCAO. JNK (c-Jun N-terminal kinase)-cJun, a pro-death pathway, also displayed the same pattern as the ERS axis. E2 treatment profoundly suppressed the impairments caused by BCCAO. Further mechanistic studies revealed that cerebral blood flow (CBF) was sharply decreased at 14 d and returned to the normal level at 21 d after BCCAO. E2 could not change CBF, while it unexpectedly enhanced the ability to carry oxygen. This is evidenced by the fact that the protein expression of haemoglobin α/β (Hα/β), an oxygen carrier, robustly increased at BCCAO 21 d and 3 m after E2 treatment. The oxygen carrier increased strongly after 21 d and 3 m of BCCAO treated with E2. Moreover, E2 correspondingly enhanced the protein expression of hypoxia-inducible factor 1α (HIF 1α) in both the early and late stage after BCCAO in the hippocampal CA1 region. Finally, E2 administration markedly decreased the activities of caspase-8, caspase-3, and caspase-12 and increased the number of NeuN-positive cells. These findings suggest that E2 serves as a neuroprotectant to alleviate VaD by suppressing ERS injury involving the haemoglobin/HIF 1α signalling pathway.

Keywords:  17β-oestradiol; Chronic cerebral hypoperfusion; Endoplasmic reticulum stress; Haemoglobin; Hypoxia-inducible factor 1α

DOI:  https://doi.org/10.1016/j.neuint.2021.105119
Cell Biosci. 2021 Jul 03. 11(1): 122

Tumor protein D52 is upregulated in oral squamous carcinoma cells under hypoxia in a hypoxia-inducible-factor-independent manner and is involved in cell death resistance.

Yuzo Abe, Yoshiki Mukudai, Mai Kurihara, Asami Houri, Junichiro Chikuda, Atsutoshi Yaso, Kosuke Kato, Toshikazu Shimane, Tatsuo Shirota.

   BACKGROUND: Tumor protein D52 (TPD52) reportedly plays an important role in the proliferation and metastasis of various cancer cells, including oral squamous cell carcinoma (OSCC) cells, and is expressed strongly at the center of the tumor, where the microenvironment is hypoxic. Thus, the present study investigated the roles of TPD52 in the survival and death of OSCC cells under hypoxia, and the relationship with hypoxia-inducible factor (HIF). We examined the expression of TPD52 in OSCC cells under hypoxic conditions and analyzed the effects of HIF on the modulation of TPD52 expression. Finally, the combinational effects of TPD52 knockdown and HIF inhibition were investigated both in vitro and in vivo.
RESULTS: The mRNA and protein levels of TPD52 increased in OSCC cells under hypoxia. However, the increase was independent of HIF transcription. Importantly, the observation was due to upregulation of mRNA stability by binding of mRNA to T-cell intercellular antigen (TIA) 1 and TIA-related protein (TIAR). Simultaneous knockdown of TPD52 and inhibition of HIF significantly reduced cell viability. In addition, the in vivo tumor-xenograft experiments showed that TPD52 acts as an autophagy inhibitor caused by a decrease in p62.
CONCLUSIONS: This study showed that the expression of TPD52 increases in OSCC cells under hypoxia in a HIF-independent manner and plays an important role in the proliferation and survival of the cells in concordance with HIF, suggesting that novel cancer therapeutics might be led by TPD52 suppression.

Keywords:  Autophagy; HIF; Hypoxia; RNA stability; Squamous cell carcinoma; TPD52

DOI:  https://doi.org/10.1186/s13578-021-00634-0
CNS Neurosci Ther. 2021 Aug;27(8): 869-882

Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases.

Jia Liu, Yakun Gu, Mengyuan Guo, Xunming Ji.

  As the organ with the highest demand for oxygen, the brain has a poor tolerance to ischemia and hypoxia. Despite severe ischemia/hypoxia induces the occurrence and development of various central nervous system (CNS) diseases, sublethal insult may induce strong protection against subsequent fatal injuries by improving tolerance. Searching for potential measures to improve brain ischemic/hypoxic is of great significance for treatment of ischemia/hypoxia related CNS diseases. Ischemic/hypoxic preconditioning (I/HPC) refers to the approach to give the body a short period of mild ischemic/hypoxic stimulus which can significantly improve the body's tolerance to subsequent more severe ischemia/hypoxia event. It has been extensively studied and been considered as an effective therapeutic strategy in CNS diseases. Its protective mechanisms involved multiple processes, such as activation of hypoxia signaling pathways, anti-inflammation, antioxidant stress, and autophagy induction, etc. As a strategy to induce endogenous neuroprotection, I/HPC has attracted extensive attention and become one of the research frontiers and hotspots in the field of neurotherapy. In this review, we discuss the basic and clinical research progress of I/HPC on CNS diseases, and summarize its mechanisms. Furthermore, we highlight the limitations and challenges of their translation from basic research to clinical application.

Keywords:  hypoxia; ischemia; neurological diseases; neuroprotection; preconditioning

DOI:  https://doi.org/10.1111/cns.13642
Biomater Sci. 2021 Jul 08.

3D printing of Cu-doped bioactive glass composite scaffolds promotes bone regeneration through activating the HIF-1α and TNF-α pathway of hUVECs.

Qiyuan Dai, Qingtao Li, Huichang Gao, Longtao Yao, Zefeng Lin, Dingguo Li, Shuangli Zhu, Cong Liu, Zhen Yang, Gang Wang, Dafu Chen, Xiaofeng Chen, Xiaodong Cao.

The increasing insight into the molecular and cellular processes within the angiogenic cascade assists in enhancing the survival and integration of engineered bone constructs. Copper-doped bioactive glass (Cu-BG) is now a potential structural component of the novel scaffolds and implants used in orthopedic and dental repairs. However, it is difficult for BG, especially micro-nano particles, to be printed into scaffolds and still retain its biological activity and ability to biodegrade. Additionally, the mechanisms of the copper-stimulating autocrine and paracrine effects of human umbilical vein endothelial cells (hUVECs) during repair and regeneration of bone are not yet clear. Therefore, in this study, we created monodispersed micro-nano spherical Cu-BG particles with varying copper content through a sol-gel process. Through in vitro tests, we found that Cu-BG enhanced angiogenesis by activating the pro-inflammatory environment and the HIF-1α pathway of hUVECs. Furthermore, 2Cu-BG diluted extracts directly promoted the osteogenic differentiation of mouse bone mesenchymal stem cells (BMSCs) in vitro. Then, a new 3D-printed tyramine-modified gelatin/silk fibroin/copper-doped bioactive glass (Gel/SF/Cu-BG) scaffold for rat bone defects was constructed, and the mechanism of the profound angiogenesis effect regulated by copper was explored in vivo. Finally, we found that hydrogel containing 1 wt% 2Cu-BG effectively regulated the spatiotemporal coupling of vascularization and osteogenesis. Therefore, Cu-BG-containing scaffolds have great potential for a wide range of bone defect repairs.

DOI: https://doi.org/10.1039/d1bm00870f
Cell Death Dis. 2021 Jul 03. 12(7): 672

SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.

Jiangyi Wang, Yun Zou, Bowen Du, Wenzhi Li, Guopeng Yu, Long Li, Lin Zhou, Xin Gu, Shangqing Song, Yushan Liu, Wenquan Zhou, Bin Xu, Zhong Wang.

Over the last decade, more than 10 independent SNPs have been discovered to be associated with the risk of renal cell carcinoma among different populations. However, the biological functions of them remain poorly understood. In this study, we performed eQTL analysis, ChIP-PCR, luciferase reporter assay, and Cox regression analysis to identify the functional role and underlying mechanism of rs67311347 in RCC. The ENCORI database, which contains the lncRNA-miRNA-mRNA interactions, was used to explore the possible target miRNA of ENTPD3-AS1. The results showed that the G > A mutation of rs67311347 created a binding motif of ZNF8 and subsequently upregulated ENTPD3-AS1 expression by acting as an enhancer. The TCGA-KIRC and our cohorts both confirmed the downregulation of ENTPD3-AS1 in RCC tissues and demonstrated that increased ENTPD3-AS1 expression was associated with good OS and PFS. Furthermore, ENTPD3-AS1 interacted with miR-155-5p and activated the expression of HIF-1α, which was an important tumor suppressor gene in the development of RCC. The functional experiments revealed that overexpression of ENTPD3-AS1 inhibited cell proliferation in RCC cell lines and the effect could be rescued by knocking down HIF-1α. Our findings reveal that SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.

DOI: https://doi.org/10.1038/s41419-021-03958-4
Cell Death Discov. 2021 Jul 08. 7(1): 176

Carcinoma associated fibroblasts small extracellular vesicles with low miR-7641 promotes breast cancer stemness and glycolysis by HIF-1α.

Yonglei Liu, Fanli Hua, Yanxia Zhan, Yanfei Yang, Jianfang Xie, Yunfeng Cheng, Feng Li.

Fibroblasts play an important role in cancer development and progression. Small extracellular vesicles (sEVs) are one type of extracellular vesicles, which mediate the interaction between cancer-associated fibroblasts and cancer cells by transferring their contents. However, the roles of sEVs from cancer-associated fibroblasts on breast cancer stem cell properties are largely unraveled. The purpose of this study was to explore the roles of sEVs from cancer-associated fibroblasts on breast cancer progression. The miRNA array data showed a different miRNA profile between CAFs sEVs and normal fibroblasts sEVs. By verification using real-time RT-PCR, the data analysis indicated that miR-7641 levels were lower in sEVs from CAFs compared with NFs. The cellular functions were assayed and the results indicated that CAFs derived sEVs with low miR-7641 levels suppressed breast cancer cell survival, glycolysis, and stem cell properties via the HIF-1α pathway. Collectively, these findings indicated that sEVs from CAFs promoted breast cancer stem cell properties and glycolysis via miR-7641/HIF-1α, which was a possible new way for targeting breast cancer.

DOI: https://doi.org/10.1038/s41420-021-00524-x