• HIF-1
• MD simulation
• binding free energy
• drug screening
• hypoxia
• p300
• phytocompounds

• HIF-1
• HIF-2
• HIFs
• Hypoxia-inducible factors
• cancer
• hypoxia

• Humans
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Discovery
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Carcinogenesis/metabolism
• Hypoxia-Inducible Factor 1/metabolism
• Hypoxia-Inducible Factor 1/antagonists & inhibitors
• Animals

• Endoperoxide
• Idiopathic Pulmonary Fibrosis
• Lung Cancer
• Prodrug
• Singlet Oxygen

• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Pyridones/chemistry
• Pyridones/pharmacology
• Pyridones/therapeutic use
• Humans
• Idiopathic Pulmonary Fibrosis/drug therapy
• Idiopathic Pulmonary Fibrosis/pathology
• Idiopathic Pulmonary Fibrosis/chemically induced
• Idiopathic Pulmonary Fibrosis/metabolism
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Animals
• Mice
• Cell Proliferation/drug effects
• Peroxides/chemistry
• Peroxides/pharmacology
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
• Cell Line, Tumor
• Molecular Structure
• Drug Screening Assays, Antitumor

• 22178048 National Natural Science Foundation of China
• 22007008 National Natural Science Foundation of China

• Humans
• Signal Transduction/drug effects
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Protein Kinase C-alpha/metabolism
• Up-Regulation/drug effects
• TOR Serine-Threonine Kinases/metabolism

• Humans
• Hypoxia-Inducible Factor 1/metabolism
• Peptides, Cyclic/pharmacology
• Peptides, Cyclic/metabolism
• Hypoxia
• Signal Transduction
• Oxygen/metabolism
• Cell Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Neoplasms/drug therapy

• AstraZeneca
• Cancer Research UK
• Engineering and Physical Sciences Research Council

• MPO
• colitis
• hypoxia
• inflammatory responses

• Animals
• Mice
• Citrobacter rodentium
• Tumor Necrosis Factor-alpha
• Peroxidase
• Hypoxia
• Bacterial Infections
• Chemokines
• Metabolism, Inborn Errors

• "Kunlun Talent High-end Innovation and Entrepreneurship Talents" Project in Qinghai Province, 2022
• 31460240 National Natural Science Foundation of China
• 2022-ZJ-905 National Natural Science Foundation of Qinghai

• Humans
• Signal Transduction
• Chemistry, Pharmaceutical
• Gene Expression Profiling
• Hypoxia

• R01 AI149852 NIAID NIH HHS
• R01 AI152416 NIAID NIH HHS

• Hypoxia-inducible factor
• Molecular characterisation
• Phylogenic tree
• Point transitions
• Single nucleotide variations (SNVs)

Patients with chronic obstructive pulmonary disease (COPD), irrespective of their smoking history, are more likely to develop lung cancer than the general population. This is mainly because COPD is characterized by chronic persistent inflammation and hypoxia, which are the risk factors for lung cancer. However, the mechanisms underlying this observation are still unknown. Hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role in the crosstalk that exists between inflammation and hypoxia. Furthermore, HIF-1α is the main regulator of somatic adaptation to hypoxia and is highly expressed in hypoxic environments. In this review, we discuss the molecular aspects of the crosstalk between hypoxia and inflammation, showing that HIF-1α is an important signaling pathway that drives COPD progression to lung cancer. Here, we also provide an overview of HIF-1α and its principal regulatory mechanisms, briefly describe HIF-1α-targeted therapy in lung cancer, and summarize substances that may be used to target HIF-1α at the level of COPD-induced inflammation.

• National Natural Science Foundation of China
• Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents

• Agence Nationale de la Recherche

The central role of an aberrantly activated EMT program in defining the critical features of aggressive carcinomas is well documented and includes cell plasticity, metastatic dissemination, drug resistance, and cancer stem cell-like phenotypes. The p53 tumor suppressor is critical for leashing off all the features mentioned above. On the molecular level, the suppression of these effects is exerted by p53 via regulation of its target genes, whose products are involved in cell cycle, apoptosis, autophagy, DNA repair, and interactions with immune cells. Importantly, a set of specific mutations in the TP53 gene (named Gain-of-Function mutations) converts this tumor suppressor into an oncogene. In this review, we attempted to contrast different regulatory roles of wild-type and mutant p53 in the multi-faceted process of EMT.

• Russian Science Foundation

Hypoxia-inducible factor-1alpha (HIF-1α) is a major transcription factor that adapts to low oxygen homeostasis and regulates the expression of several hypoxic genes, which aid in cancer survival and development. It has recently piqued the interest of translational researchers in the disciplines of cancer sciences. Hypoxia triggers an ample adaptive mechanism mediated via the HIF-1α transcriptional domain. Anaerobic glycolysis, angiogenesis, metastasis, and mitophagy are adaptive mechanisms that support tumor survival by promoting oxygen supply and regulating oxygen demand in hypoxic tumor cells. Throughout this pathway, the factor-inhibiting HIF-1α is a negative regulator of HIF-1α leading to its hydroxylation at the C-TAD domain of HIF-1α under normoxia. Thus, hydroxylated HIF-1α is unable to proceed with the transcriptional events due to interference in binding of C-TAD and CBP/p300. From this review, we can hypothesize that remodeling of FIH-1 activity is a unique mechanism that decreases the transcriptional activity of HIF-1α and, as a result, all of its hypoxic consequences. Hence, this review manuscript details the depth of knowledge of FIH-1 on hypoxia-associated cellular and molecular events, a potential strategy for targeting hypoxia-induced malignancies.

• NADPH Oxidase 4
• Pancreatic cancer
• Reactive oxygen species

• Animals
• Hydrogen Peroxide
• Mice
• NADPH Oxidase 4
• NADPH Oxidases
• Pancreatic Neoplasms
• Reactive Oxygen Species

Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O₂)‐deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments. Our data illustrates that Carbonic Anhydrases IX and XII (CA IX/XII) are critical for leukaemic cell survival in the O₂‐deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O₂ conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O₂‐deprived settings, we sought to elucidate the role of dual CA IX/XII inhibition as a novel strategy to eliminate AML cells under hypoxic conditions. Our findings demonstrate that the dual CA IX/XII inhibitor FC531 may prove to be of value as an adjunct to chemotherapy for the treatment of AML.

• Carbonic Anhydrases
• acute myeloid leukemia
• drug resistance
• hypoxia
• pH regulation

Papillomaviruses, polyomaviruses and adenoviruses are collectively categorized as the small DNA tumour viruses. Notably, human adenoviruses were the first human viruses demonstrated to be able to cause cancer, albeit in non-human animal models. Despite their long history, no human adenovirus is a known causative agent of human cancers, unlike a subset of their more famous cousins, including human papillomaviruses and human Merkel cell polyomavirus. Nevertheless, seminal research using human adenoviruses has been highly informative in understanding the basics of cell cycle control, gene expression, apoptosis and cell differentiation. This review highlights the contributions of human adenovirus research in advancing our knowledge of the molecular basis of cancer.

• E1A
• E1B
• E4
• Hallmarks of cancer
• Human adenovirus
• Transformation

• Acetylation
• Animals
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Gene Expression Regulation
• Histone-Lysine N-Methyltransferase/metabolism
• Humans
• Hypoxia/genetics
• Hypoxia/metabolism
• Methylation
• Mice
• Mice, Knockout
• Models, Animal
• Promoter Regions, Genetic
• Protein Binding

• FC001501 Wellcome Trust
• NIHR-RP-2016-06-004 Department of Health
• 106241 Wellcome Trust
• FC001501 Medical Research Council
• FC001501 Wellcome Trust
• FC001501 Cancer Research UK
• FC001501 Cancer Research UK
• FC001501 Medical Research Council
• 215477/Z/19/Z Wellcome Trust
• 106241/Z/14/Z Wellcome Trust
• 16016 Cancer Research UK
• 096956/Z/11/Z Wellcome Trust
• 096956 Wellcome Trust
• 203141/Z/16/Z Wellcome Trust
• FC001501 Arthritis Research UK
• 215477 Wellcome Trust
• Wellcome Trust

• Cellular stress
• DNA damage Response
• Heat shock
• Hypoxia
• Oxidative stress
• Unfolded protein response

• Chromatin/genetics
• Environmental Pollutants/toxicity
• Heat-Shock Response
• Humans
• Oxidation-Reduction
• Oxidative Stress/genetics

• K01 ES032044 NIEHS NIH HHS

• Detection
• Fluorescent probe
• Hypoxia
• Imaging
• Nitroreductase

• fluorescence imaging
• breast cancer
• cancer microenvironment
• cancer models

• Animals
• Breast Neoplasms/physiopathology
• Carcinogenesis
• Cell Culture Techniques
• Macrophages/physiology
• Mice
• Tumor Cells, Cultured/physiology
• Tumor Microenvironment

• 75N91019D00024 NCI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.

• HepG2 cells
• amino acid metabolism
• estradiol
• estrogen receptor
• gene–metabolite interaction
• genomics
• glycolysis
• metabolomics
• oxidative phosphorylation

• Cell Count
• Cell Proliferation/drug effects
• Deoxyglucose/pharmacology
• Estradiol/pharmacology
• Estrogens/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Hep G2 Cells
• Humans
• Liver Neoplasms/metabolism
• Metabolic Networks and Pathways/drug effects
• Metabolome/drug effects
• Metabolomics
• Nitriles/pharmacology
• Oligomycins/pharmacology
• Pyrazoles/pharmacology
• Receptors, Estrogen/metabolism
• Transcriptome/genetics

• R35 GM133510 NIGMS NIH HHS

Cancer cells in solid tumors often experience lack of oxygen (hypoxia), which they overcome with the help of hypoxia inducible transcription factors (HIFs). When HIFs are activated, they stimulate the expression of many genes and cause the production of proteins that help cancer cells grow and migrate even in the presence of very little oxygen. Many experiments have shown that agents that block the activity of HIFs (HIF inhibitors) can prevent growth of cancer cells under hypoxia and, subsequently, hinder formation of malignant tumors or metastases. Most small chemical HIF inhibitors lack the selectivity required for development of safe anticancer drugs. On the other hand, peptides derived from HIFs themselves can be very selective HIF inhibitors by disrupting specific associations of HIFs with cellular components that are essential for HIF activation. This review discusses the nature of available peptide HIF inhibitors and their prospects as effective pharmaceuticals against cancer.

Reduced oxygen availability (hypoxia) is a characteristic of many disorders including cancer. Central components of the systemic and cellular response to hypoxia are the Hypoxia Inducible Factors (HIFs), a small family of heterodimeric transcription factors that directly or indirectly regulate the expression of hundreds of genes, the products of which mediate adaptive changes in processes that include metabolism, erythropoiesis, and angiogenesis. The overexpression of HIFs has been linked to the pathogenesis and progression of cancer. Moreover, evidence from cellular and animal models have convincingly shown that targeting HIFs represents a valid approach to treat hypoxia-related disorders. However, targeting transcription factors with small molecules is a very demanding task and development of HIF inhibitors with specificity and therapeutic potential has largely remained an unattainable challenge. Another promising approach to inhibit HIFs is to use peptides modelled after HIF subunit domains known to be involved in protein–protein interactions that are critical for HIF function. Introduction of these peptides into cells can inhibit, through competition, the activity of endogenous HIFs in a sequence and, therefore also isoform, specific manner. This review summarizes the involvement of HIFs in cancer and the approaches for targeting them, with a special focus on the development of peptide HIF inhibitors and their prospects as highly-specific pharmacological agents.

• HIF
• HIF inhibition
• HIF-1α
• hypoxia
• peptide inhibitors

Cancer cells change their metabolism to support a chaotic and uncontrolled growth. In addition to meeting the metabolic needs of the cell, these changes in metabolism also affect the patterns of gene activation, changing the identity of cancer cells. As a consequence, cancer cells become more aggressive and more resistant to treatments. In this article, we present a review of the literature on the interactions between metabolism and cell identity, and we explore the mechanisms by which metabolic changes affect gene regulation. This is important because recent therapies under active investigation target both metabolism and gene regulation. The interactions of these new therapies with existing chemotherapies are not known and need to be investigated.

Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.

• cancer epigenetics
• cancer metabolism
• cell differentiation in cancer
• mitochondrial metabolism

• Apoptosis
• Ferroptosis
• HDACi
• Pyroptosis
• Quisinostat
• p53

Cellular transplantation is in clinical testing for a number of central nervous system disorders, including spinal cord injury (SCI). One challenge is acute transplanted cell death. To prevent this death, there is a need to both establish when the death occurs and develop approaches to mitigate its effects. Here, using luciferase (luc) and green fluorescent protein (GFP) expressing Schwann cell (SC) transplants in the contused thoracic rat spinal cord 7 d postinjury, we establish via in vivo bioluminescent (IVIS) imaging and stereology that cell death occurs prior to 2–3 d postimplantation. We then test an alternative approach to the current paradigm of enhancing transplant survival by including multiple factors along with the cells. To stimulate multiple cellular adaptive pathways concurrently, we activate the hypoxia-inducible factor 1α (HIF-1α) transcriptional pathway. Retroviral expression of VP16-HIF-1α in SCs increased HIF-α by 5.9-fold and its target genes implicated in oxygen transport and delivery (VEGF, 2.2-fold) and cellular metabolism (enolase, 1.7-fold). In cell death assays in vitro, HIF-1α protected cells from H₂O₂-induced oxidative damage. It also provided some protection against camptothecin-induced DNA damage, but not thapsigargin-induced endoplasmic reticulum stress or tunicamycin-induced unfolded protein response. Following transplantation, VP16-HIF-1α increased SC survival by 34.3%. The increase in cell survival was detectable by stereology, but not by in vivo luciferase or ex vivo GFP IVIS imaging. The results support the hypothesis that activating adaptive cellular pathways enhances transplant survival and identifies an alternative pro-survival approach that, with optimization, could be amenable to clinical translation.

• Schwann cells
• cell survival
• in vivo imaging
• spinal cord injury
• transcription factor
• transplant

• Anaerobic
• Anoxic
• Chlamydia
• Elementary body
• Inclusions
• Life cycle
• Reticulate body

Proton pump inhibitor (PPI) and other acid-suppressing drugs are widely used in the treatment of gastrointestinal ulcer, upper gastrointestinal bleeding, gastritis, and gastric cancer (GC). About 80% of GC patients receive acid suppression treatment. PPI suppresses the production of gastric acid by inhibiting the function of H⁺/K⁺-ATPase in gastric parietal cells and raises the pH value to achieve therapeutic purposes. Some studies have found that PPI had a certain antitumor effect in the proliferation and apoptosis of tumor cells. But the effects of environmental pH on the growth of GC cells and its mechanism are unknown. Therefore, we hoped to find the effects of culture medium pH on the biological behavior of GC cells by in vitro experiments and provide guidance for the use of acid-suppressing drugs in GC patients.

We aimed to observe the effects of pH changes in GC cell culture medium on the cell biological behavior of cancer cells and to analyze the potential mechanisms. We hoped to find out the effect of acid suppression on the growth of GC cells.

The GC cell lines (SGC-7901 and MKN45) were used as the research object. We adjusted the pH value in the cell culture medium to observe the changes in cell viability (MTT), apoptosis (flow cytometry), and invasion (Transwell) at pH 6, pH 7, and pH 8. qRT-PCR and western blot (WB) assays were used to determine the expression changes of genes and proteins (mTOR, AKT, Wnt, Glut, and HIF-1α) at pH 6, pH 7, and pH 8.

The results of MTT showed that the viability of SGC-7901 and MKN45 in the pH 8.0 group was significantly weaker than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (α) at pH 6, pH 7, and pH 8. P < 0.001). Flow cytometry results showed that the apoptosis of SGC-7901 and MKN45 in the pH 8.0 group was more obvious than that in the pH 6.0 or pH 7.0 group (

Compared with the microacid environment, the microalkaline environment inhibited the viability, invasion, and expression of genes and proteins (mTOR, AKT, Wnt, Glut, and HIF-1α) but promoted the apoptosis of GC cells and thus inhibited the growth of GC.α) at pH 6, pH 7, and pH 8.

• hydroxylation
• hypoxia
• metalloenzymes
• oxygen
• transcription

For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation.

• arteriovenous fistula
• hypoxia
• hypoxia-inducible factor
• metabolism
• neointimal hyperplasia

• Arteriovenous Fistula/metabolism
• Cell Proliferation
• Constriction, Pathologic
• Hemodynamics
• Humans
• Hyperplasia/metabolism
• Hypoxia/metabolism
• Ischemia
• Kidney Diseases
• Neointima/metabolism
• Renal Dialysis
• Renal Insufficiency, Chronic
• Vascular Diseases
• Veins/pathology

• hypoxia-inducible factor-1α
• pulsatility index
• resistance index

• Antiproliferation
• Apoptosis
• Autophagy
• Cell death
• Cytotoxic
• Marine bioactive compounds

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Aquatic Organisms/chemistry
• Biological Products/chemistry
• Biological Products/pharmacology
• Biological Products/therapeutic use
• Clinical Trials as Topic
• Drug Approval
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Neoplasms/drug therapy

Previous experimental studies have established that MicroRNAs (miRNAs) can function as oncogenes or tumor suppressors in the regulation of tumor biology or pathology. However, the effects of ionizing radiation (IR) on the expression levels of cellular miRNAs and their further effects on the biological behavior of tumor cells require further investigation.

We determined the proliferation, migration and tube formation of HUVEC cells after ionizing radiation (control, 0h and 24h), and the changes of miR-21, VEFG and HIF-1α levels after ionizing radiation were measured by Western blot (WB). The effects of miR-21 mimics and inhibitors on the protein and mRNA expression of PTEN were determined by RT-PCT and WB. Two independent luciferase reporter plasmids were constructed to detect changes in PTEN protein expression.

We found that both IR and miR-21 increase proliferation, migration and tube formation of HUVEC cells. Ionizing radiation directly targets the inhibition of PTEN expression by causing an increase in miR-21 expression, and induces the accumulation of VEGF and HIF-1α expression in cells by the PI3K / AKT signaling pathway. Simultaneous induction of ectopic expression of PTEN can rescue radiation-induced proliferation, migration and tube formation in tumor cells.

miR-21 promotes tumor cell proliferation and migration by targeting inhibition of PTEN expression, which may become a potential target for tumor therapy in the future.

• MicroRNA 21
• angiogenesis
• PTEN
• ionization
• HIF-1α

• AQ4N
• H2O2 circular amplification
• H2O2-responsiveness
• glucose oxidase
• synergistic cancer therapy

• Animals
• Anthraquinones/chemistry
• Anthraquinones/pharmacology
• Anthraquinones/therapeutic use
• Catalysis
• Cell Line, Tumor
• Cell Survival/drug effects
• Glucose/chemistry
• Glucose/metabolism
• Glucose Oxidase/chemistry
• Glucose Oxidase/metabolism
• Humans
• Hydrogen Peroxide/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Mice
• Mice, Nude
• Nanotechnology/instrumentation
• Nanotechnology/methods
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Oxidation-Reduction
• Polyesters/chemistry
• Polyethylene Glycols/chemistry
• Prodrugs/chemistry
• Prodrugs/pharmacology
• Prodrugs/therapeutic use
• Protein Carbonylation
• Tumor Microenvironment

• 81871483 Natural Science Foundation of China
• 81601538 Natural Science Foundation of China
• 81671813 Natural Science Foundation of China
• U1505221 Natural Science Foundation of China
• 61727823 Natural Science Foundation of China
• 61575044 Natural Science Foundation of China
• 2016Y9062 Joint Funds for the innovation of science and Technology
• 2016Y9061 Joint Funds for the innovation of science and Technology
• 2017-ZQN-75 Scientific Foundation of the Fujian provincial Health and Family Planning Commission
• 2018-ZQN-75 Scientific Foundation of the Fujian provincial Health and Family Planning Commission
• WKJ2016-2-15 Joint Research Projects of Health and Education Commission of Fujian Province

• Cancer therapy
• HIF-1
• HIF-1α/HIF-1β hetero-dimerization
• HIF-1α/p300
• PPIs
• Small molecular inhibitors

• Cell Hypoxia/drug effects
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Models, Molecular
• Molecular Conformation
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Binding/drug effects
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology

• Cancer
• Cell-penetrating peptides
• ERK1/2
• HIF-1
• Hypoxia

• Amino Acid Sequence
• Apoptosis/drug effects
• Apoptosis/genetics
• Apoptosis/physiology
• Cell Hypoxia
• Cell Line, Tumor
• Cell-Penetrating Peptides/genetics
• Cell-Penetrating Peptides/metabolism
• Cell-Penetrating Peptides/pharmacology
• Extracellular Signal-Regulated MAP Kinases/genetics
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• HeLa Cells
• Hep G2 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Nuclear Export Signals/genetics
• Recombinant Fusion Proteins/genetics
• Recombinant Fusion Proteins/metabolism
• Recombinant Fusion Proteins/pharmacology
• Sequence Homology, Amino Acid
• tat Gene Products, Human Immunodeficiency Virus/genetics

• HYPOXYTARGET 3129 European Social Fund (ESF) and National Resources
• 5360 Fondation Santé
• Fondation Santé

The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) in vitro model. To directly assess the unique and overlapping functions of HIF-1α and HIF-2α, we use CRISPR gene-editing to generate isogenic H1299 non-small cell lung carcinoma cells lacking HIF-1α, HIF-2α or both. We found that in HIF1 knockout cells, HIF-2α was strongly induced by hypoxia compared to wild type but the reverse was not seen in HIF2 knockout cells. Cells lacking HIF-1α were more radiation resistant than HIF2 knockout and wildtype cells upon hypoxia, which was associated with a reduced recruitment of γH2AX foci directly after irradiation and not due to differences in proliferation. Conversely, double-HIF1/2 knockout cells were most radiation sensitive and had increased γH2AX recruitment and cell cycle delay. Compensatory HIF-2α activity in HIF1 knockout cells is the main cause of this radioprotective effect. Under hypoxia, HIF1 knockout cells uniquely had a strong increase in lactate production and decrease in extracellular pH. Using genetically identical HIF-α isoform-deficient cells we identified a strong radiosensitizing of HIF1, but not of HIF2, which was associated with a reduced extracellular pH and reduced glycolysis.

• HIF
• hypoxia
• metabolism
• radiotherapy

• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/physiology
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Cell Line, Tumor
• Gene Knockout Techniques
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/physiology
• Lung Neoplasms/genetics
• Lung Neoplasms/radiotherapy
• Radiation Tolerance/genetics

• HGF
• HIF
• MET
• VEGF
• angiogenesis

Cholangiocarcinoma (CCA) is a relatively rare malignant and lethal tumour derived from bile duct epithelium and the morbidity is now increasing worldwide. This disease is difficult to diagnose at its inchoate stage and has poor prognosis. Therefore, a clear understanding of pathogenesis and major influencing factors is the key to develop effective therapeutic methods for CCA. In previous studies, canonical correlation analysis has demonstrated that tumour microenvironment plays an intricate role in the progression of various types of cancers including CCA. CCA tumour microenvironment is a dynamic environment consisting of authoritative tumour stromal cells and extracellular matrix where tumour stromal cells and cancer cells can thrive. CCA stromal cells include immune and non‐immune cells, such as inflammatory cells, endothelial cells, fibroblasts, and macrophages. Likewise, CCA tumour microenvironment contains abundant proliferative factors and can significantly impact the behaviour of cancer cells. Through abominably intricate interactions with CCA cells, CCA tumour microenvironment plays an important role in promoting tumour proliferation, accelerating neovascularization, facilitating tumour invasion, and preventing tumour cells from organismal immune reactions and apoptosis. This review summarizes the recent research progress regarding the connection between tumour behaviours and tumour stromal cells in CCA, as well as the mechanism underlying the effect of tumour stromal cells on the growth of CCA. A thorough understanding of the relationship between CCA and tumour stromal cells can shed some light on the development of new therapeutic methods for treating CCA.

• cholangiocarcinoma
• tumor microenvironment
• tumor stromal cells

• Cancer cell metastasis
• Chitin synthesis inhibitors (CSIs)
• Hypoxia-inducible factor 1α (HIF-1α)

• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/pathology
• Chitin/antagonists & inhibitors
• Chitin/chemical synthesis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Liver Neoplasms/etiology
• Liver Neoplasms/pathology
• Neoplasm Metastasis

• HIF-1
• LXY7824
• analogue
• inhibition

• Animals
• Antineoplastic Agents/chemical synthesis
• Cell Line, Tumor
• Drug Design
• Drug Screening Assays, Antitumor
• Female
• Humans
• Hypoxia-Inducible Factor 1/antagonists & inhibitors
• Mice, Inbred BALB C
• Mice, Nude

• cancer microenvironment
• cancer stem cells
• epigenetics
• epithelial-mesenchymal transition
• hypoxia
• metastasis

• Disease model
• Embryonic development
• Histone acetylation
• Rescue
• Rubinstein Taybi Syndrome (RSTS)
• Zebrafish
• ep300