• NIS
• hsa_circ_0023990
• hypoxia inhibitor
• iodine uptake disorder
• thyroid cancer

• 81960321 National Natural Science Foundation of China
• 82260356 National Natural Science Foundation of China
• 20232ACB206026 Natural Science Foundation of Jiangxi Province

• Aerobic glycolysis
• Carcinoma
• Dedifferentiation
• HIF-1α

• Cancer
• Telomere shortening
• Telomeres

• ZYYCXTD-C-202205 the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine
• CI2021B009 the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences
• HLCMHPP2023085 the High Level Chinese Medical Hospital Promotion Project
• HLCMHPP202308506 the High Level Chinese Medical Hospital Promotion Project
• HLCMHPP2023005 the High Level Chinese Medical Hospital Promotion Project
• 81774294 the National Natural Science Foundation of China
• 82104961 the National Natural Science Foundation of China
• ZZ14-YQ-016 the Fundamental Research Funds for the Central public welfare research institutes
• ZZ13-YQ-028 the Fundamental Research Funds for the Central public welfare research institutes
• CI2021A01816 CACMS Innovation Fund
• CI2021A01814 CACMS Innovation Fund
• CI2021A01805 CACMS Innovation Fund

• (HIF)-1α/2
• Hypoxia-inducible factor inhibitors
• anticancer agents
• hypoxia
• structure activity relationship
• tumor

• Humans
• Antineoplastic Agents/pharmacology
• Neoplasms/drug therapy
• Neoplasms/pathology
• Drug Discovery/methods
• Animals
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors
• Basic Helix-Loop-Helix Transcription Factors/drug effects
• Drug Development
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
• Molecular Targeted Therapy
• Hypoxia-Inducible Factor 1/antagonists & inhibitors
• Hypoxia-Inducible Factor 1/metabolism

• Angiogenesis
• Chronic lymphocytic leukemia
• Inflammation
• Interleukin-6
• Neovascularization

• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
• Leukemia, Lymphocytic, Chronic, B-Cell/pathology
• Neovascularization, Pathologic/metabolism
• Female
• Male
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Vascular Endothelial Growth Factor A/metabolism
• Aged
• Middle Aged
• Inflammation/metabolism
• Signal Transduction
• Interleukin-6/metabolism
• Nitric Oxide Synthase Type III/metabolism
• Aged, 80 and over
• Adult
• Angiogenesis

• B-cells
• CRISPR/Cas9
• Cell viability
• Gene expression
• Hypoxia
• Leukemia
• miRNA

• START/MED/089 and PRIMUS/17/MED/16 Elena Golovina
• START/MED/089 Tomas Heizer
• START/MED/089 Lenka Daumova
• PROGRES Q26/LF1 Martin Bajecny
• IG21408 Simona Fontana
• IG21408 Valentina Griggio
• IG21408 Rebecca Jones
• IG21408 Marta Coscia
• IG21408 Chiara Riganti
• START/MED/089 and PRIMUS/17/MED/16 Karina Savvulidi Vargova

• Invasion
• Lung cancer
• Molecular interaction
• TP53

• Female
• Humans
• Male
• Middle Aged
• Cell Line, Tumor
• Desmoglein 3/genetics
• Desmoglein 3/metabolism
• Gene Expression Regulation, Neoplastic
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Mutation
• Neoplasm Invasiveness
• Prognosis
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• LHGJ20190740 Joint Co-construction Project of Henan Medical Science and Technology Research Plan

• CLL pathogenesis
• Homing
• Inflammation
• Proliferation
• Survival
• Tumor microenvironment

• Humans
• Tumor Microenvironment/immunology
• Leukemia, Lymphocytic, Chronic, B-Cell/immunology
• Leukemia, Lymphocytic, Chronic, B-Cell/pathology
• Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
• Signal Transduction/immunology
• Extracellular Vesicles/immunology
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/pathology

• Cancer Cell Metabolism
• Hematological malignancies
• Hypoxia-Inducible Factor-1 (HIF-1)
• Metabolic Reprogramming
• cancer therapeutics

• Humans
• Leukemia/metabolism
• Leukemia/pathology
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Hypoxia-Inducible Factor 1/metabolism
• Animals
• Signal Transduction

• Angiogenesis
• Hematological malignancies
• Hypoxia-inducible factor-1 alpha (HIF-1α)
• Immune escape
• Targeted therapy

• CD4(+)T cell
• EAMG inflammation model
• HIF-1α
• IL-6-dependent STAT3 axis
• Immune imbalance
• Regulatory mechanism

• Animals
• Immunity, Humoral
• Interleukin-6/pharmacology
• T-Lymphocyte Subsets
• Th1 Cells
• Myasthenia Gravis, Autoimmune, Experimental/drug therapy
• Myasthenia Gravis, Autoimmune, Experimental/pathology
• Inflammation/drug therapy

• chronic lymphocytic leukaemia
• targeted therapies

• Animals
• Mice
• Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
• Leukemia, Lymphocytic, Chronic, B-Cell/pathology
• Cell Line, Tumor
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Hydrazines/pharmacology
• Hydrazines/therapeutic use
• Drug Combinations
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use

• AIRC
• Karyopharm Therapeutics
• University of Torino

• B cells
• B-CLL
• HIF-1α
• Immunometabolism
• TLR7/8 agonist
• mTOR

• Alexandria University

• hyperbaric oxygen
• hypoxia-inducing factors 1α
• immunotherapy
• reactive oxygen species
• tumor microenvironment

• Myocardial Infarction Associated Transcript (MIAT)
• gene expression
• leukemia
• lncRNA
• non-coding RNA

• hif-1α
• ki67
• locally advanced cervical cancer (lacc)
• nact
• vegf-a

• Female
• Humans
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Chemotherapy, Adjuvant
• Ki-67 Antigen/genetics
• Neoadjuvant Therapy
• Neoplasm Staging
• Uterine Cervical Neoplasms/drug therapy
• Uterine Cervical Neoplasms/pathology
• Vascular Endothelial Growth Factor A/genetics

• CLL
• p53
• phosphorylation

• HIF - 1α
• HIF - 2, αhypoxia, inducible-factor
• bone marrow
• hypoxic stress
• leukemia

• Ministero della Salute

• CLL
• EGLN1
• hypoxia-inducible factor prolyl hydroxylase (HIF-PH)
• molidustat

• 81670160, 81800198 and 82070175 National Natural Science Foundation of China

It has been unclear what role metabolism is playing in the pathophysiology of chronic lymphocytic leukemia (CLL). One reason is that the study of CLL metabolism is challenging due to the resting nature of circulating CLL cells. Also, it is not clear if any of the genomic aberrations observed in this disease have any impact on metabolism. Here, we demonstrate that CLL cells in proliferation centers exhibit upregulation of several molecules involved in glycolysis and mitochondrial metabolism. Comparison of CXCR4/CD5 intraclonal cell subpopulations showed that these changes are paralleled by increases in the metabolic activity of the CXCR4^lowCD5^high fraction that have recently egressed from the lymph nodes. Notably, anti-IgM stimulation of CLL cells recapitulates many of these metabolic alterations, including increased glucose uptake, increased lactate production, induction of glycolytic enzymes, and increased respiratory reserve. Treatment of CLL cells with inhibitors of B-cell receptor (BCR) signaling blocked these anti-IgM-induced changes in vitro, which was mirrored by decreases in hexokinase 2 expression in CLL cells from ibrutinib-treated patients in vivo. Interestingly, several samples from patients with 17p-deletion manifested increased spontaneous aerobic glycolysis in the unstimulated state suggestive of a BCR-independent metabolic phenotype. We conclude that the proliferative fraction of CLL cells found in lymphoid tissues or the peripheral blood of CLL patients exhibit increased metabolic activity when compared with the bulk CLL-cell population. Although this is due to microenvironmental stimulatory signals such as BCR-engagement in most cases, increases in resting metabolic activity can be observed in cases with 17p-deletion.

Hypoxia-inducible factor-1α (HIF-1α) is widely distributed in human cells, and it can form different signaling pathways with various upstream and downstream proteins, mediate hypoxia signals, regulate cells to produce a series of compensatory responses to hypoxia, and play an important role in the physiological and pathological processes of the body, so it is a focus of biomedical research. In recent years, various types of HIF-1α inhibitors have been designed and synthesized and are expected to become a new class of drugs for the treatment of diseases such as tumors, leukemia, diabetes, and ischemic diseases. This article mainly reviews the structure and functional regulation of HIF-1α, the modes of action of HIF-1α inhibitors, and the application of HIF-1α inhibitors during the treatment of diseases.

• HIF-1α
• HIF-1α inhibitor
• disease treatment
• leukemia
• tumor

Cell death can occur in different modes, ferroptosis, pyroptosis, apoptosis, and necroptosis. Recent studies have shown that pyroptosis can be effectively regulated and that like necroptosis, pyroptosis has been regarded as a type of programmed cell death. The mechanism of its occurrence can be divided into canonical inflammasome-induced pyroptosis and noncanonical inflammasome-induced pyroptosis. In the past research, pyroptosis has been shown to be closely related to various diseases, such as tumors, neurodegenerative diseases, and central nervous system trauma, and studies have pointed out that in central nervous system trauma, pyroptosis is activated. Furthermore, these studies have shown that the inhibition of pyroptosis can play a role in protecting nerve function. In this review, we summarized the mechanisms of pyroptosis, introduce treatment strategies for targeted pyroptosis in central nervous system trauma, and proposed some issues of targeted pyroptosis in the treatment of central nervous system injury.

• National Natural Science Foundation of China

• Apoptosis
• Autophagy
• Hypertrophic scar
• Hypoxia-inducible factor-1α (HIF-1α)
• p53

The transcription factor, hypoxia‐inducible factor‐1α (HIF‐1α), has previously been shown to upregulate the expression of hypoxia‐related genes, including erythropoietin (EPO). However, the role of hypoxia‐inducible factor‐1α in morphogenesis during salivary gland development is unclear. We investigated the function of HIF‐1α in submandibular gland (SMG) organ cultures obtained from embryonic day 13.5 embryos from ICR female mice. Expression of HIF‐1α, glucose transporter 1, and vascular endothelial growth factor was induced under hypoxia (5% O₂). We further showed that BAY 87‐2243‐mediated inhibition of HIF‐1α suppressed salivary gland development. Under severe hypoxia (1% O₂), HIF‐1α did not promote salivary gland development; this was due to suppression of cell proliferation and inhibition of the cell cycle and not because of autophagy and apoptosis. Additionally, using the inhibitor U0126, we verified that the ERK1/2 pathway is upstream of HIF‐1α. Overall, we found that the HIF‐1α signaling pathway plays a critical role in salivary gland development in ex vivo SMG organ cultures.

• HIF-1α
• development
• hypoxia
• salivary glands

• CLL
• Chronic Lymphocytic Leukemia
• Ibrutinib
• Immune function

• Humans
• Immunotherapy/methods
• Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy

• N/A Janssen-Cilag, S.A.
• Janssen-Cilag, S.A.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, mostly affecting the elderly. The survival of leukemic cells depends on multiple soluble factors and on the stimulation of the BCR signaling pathway. Microenvironment-dependent transcription factors also contribute to CLL biology. Here, we generated new transgenic murine conditional knock-out models of CLL to study the role of the two transcription factors HIF-1α and AHR. Unexpectedly, we observed that both factors are dispensable for leukemia development in these models.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1α are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1α being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL.

• AHR
• HIF1α
• chronic lymphocytic leukemia
• tumor microenvironment

In chronic lymphocytic leukemia (CLL), immune alterations—affecting both the innate and adaptive immunity—are very common. As a clinical consequence, patients with CLL frequently present with autoimmune phenomena, increased risk of infections and second malignancies. The aim of this review article is to present available data on CLL-associated alterations of immune parameters that correlate with known prognostic markers and with clinical outcome. Also, data on the impact of immune-related clinical manifestations on the prognosis of patients with CLL will be discussed.

Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL-related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis.

• chronic lymphocytic leukemia
• immune dysfunctions
• prognosis

• Cancer stem cells
• Neural crest
• Neuroblastoma
• Polyploid giant cancer cells molecular mechanisms
• Therapeutic targeting
• Tumour microenvironment

• CXCL12/CXCR4 axis
• chronic lymphocytic leukemia
• drug resistance
• hypoxia inducible factor-1α
• tumor microenvironment

The microenvironment that surrounds a tumor, in addition to the tumor itself, plays an important role in the onset of resistance to molecularly targeted therapies. Cancer cells and their microenvironment interact closely between them by means of a molecular communication that mutually influences their biological characteristics and behavior. Leukemia cells regulate the recruitment, activation and program of the cells of the surrounding microenvironment, including those of the immune system. Studies on the interactions between the bone marrow (BM) microenvironment and Acute Lymphoblastic Leukemia (ALL) cells have opened a scenario of potential therapeutic targets which include cytokines and their receptors, signal transduction networks, and hypoxia-related proteins. Hypoxia also enhances the formation of new blood vessels, and several studies show how angiogenesis could have a key role in the pathogenesis of ALL. Knowledge of the molecular mechanisms underlying tumor-microenvironment communication and angiogenesis could contribute to the early diagnosis of leukemia and to personalized molecular therapies. This article is part of a Special Issue entitled: Innovative Multi-Disciplinary Approaches for Precision Studies in Leukemia edited by Sandra Marmiroli (University of Modena and Reggio Emilia, Modena, Italy) and Xu Huang (University of Glasgow, Glasgow, United Kingdom).

• ALL
• HIF
• angiogenesis
• bone marrow
• hypoxia
• microenvironment
• therapies

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with intense cytogenetic aberrations. Importantly, our recent report indicated that thyroid hormone receptor interactor 13 (TRIP13) is a potential new therapeutic target in CLL. In this study, we predicted 20 TRIP13-related genes and found that KIAA0101 is a novel gene that regulates cell proliferation and the cell cycle of CLL cells.

CD19⁺ B cells were isolated from the peripheral blood of 26 CLL patients and 6 healthy donors through magnetic cell sorting. Cell proliferation was assessed by the CCK-8 assay. The mRNA and protein levels of genes were examined through RT-qPCR and western blot assays, respectively. Cell cycle and cell apoptosis were measured through Annexin V-based flow cytometry and the caspase 3/7 activity assay. Potential targets of KIAA0101 were identified through microarray analysis. 20 TRIP13 related genes was predicted by Ingenuity Pathway Analysis (IPA). KIAA0101-regulated functions and molecular pathways were predicted through IPA.

KIAA0101 knockdown had the strongest inhibitory effect on CLL cell proliferation among the 20 TRIP13-related genes. KIAA0101 was highly expressed in CD19⁺ B cells of CLL patients. KIAA0101 knockdown induced cell cycle arrest and cell apoptosis, and inhibited FOXO1, MYD88, and TLR4 expression in CLL cells.

Taken together, we demonstrated that KIAA0101 plays a critical role in cell proliferation and the cell cycle of human CLL cells. KIAA0101 knockdown induced cell apoptosis, and reduced FOXO1, MYD88, and TLR4 expression, and may therefore be used as a therapeutic target of CLL.

• Chronic lymphocytic leukemia (CLL)
• KIAA0101
• apoptosis
• cycle
• proliferation

IGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis.

The co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by ‘WGCNA’ package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan–Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes.

2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA.

The expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.

• Chronic lymphocytic leukemia
• Gene expression profile
• IGHV mutation
• Survival analysis

• Chemoresistance
• Endoplasmic reticulum stress
• Hypoxia
• Hypoxia-inducible factor-1α
• Unfolded protein response

• cancer
• chemoresistance
• hypoxia
• metabolic reprogramming

• Amino Acids/metabolism
• Animals
• Citric Acid Cycle
• Dimerization
• Disease Progression
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition
• Glucose/metabolism
• Glutamine/metabolism
• Humans
• Hypoxia/metabolism
• Lactic Acid/metabolism
• Mice
• Mitochondria/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Oxidation-Reduction
• Oxidative Phosphorylation
• Oxygen/metabolism
• Phenotype
• Reactive Oxygen Species/metabolism
• Tumor Microenvironment

• SOX9
• aggrecan
• baicalin
• collagen type 2
• extracellular matrix
• hypoxia inducible factor-1α

The von Hippel–Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel–Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein–protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis.

• VHL disease
• angiogenesis
• cancerogenesis
• hypoxia response
• protein degradation
• tumour suppressor

• Alternative splicing
• Cancer hallmarks
• Hypoxia

• Alternative Splicing
• Disease Progression
• Epithelial-Mesenchymal Transition
• Humans
• Hypoxia/physiopathology
• Neoplasms/genetics
• Neoplasms/pathology

• EZN-2208
• chronic lymphocytic leukaemia
• fludarabine
• hypoxia-inducible factors