scholarly journals Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 27 ◽  
Author(s):  
Dominik A. Barth ◽  
Felix Prinz ◽  
Julia Teppan ◽  
Katharina Jonas ◽  
Christiane Klec ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Protein Coding ◽  
Rna Molecules ◽  
Von Hippel Lindau ◽  
Hypoxic Conditions ◽  
Main Regulator ◽  
Upstream Regulators

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

The role of iron and 2-oxoglutarate oxygenases in signalling

2003 ◽  
Vol 31 (3) ◽  
pp. 510-515 ◽  
Author(s):  
K.S. Hewitson ◽  
L.A. McNeill ◽  
J.M. Elkins ◽  
C.J. Schofield
Keyword(s):  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Transactivation Domain ◽  
Von Hippel Lindau ◽  
Helix Loop Helix ◽  
Hypoxic Conditions ◽  
Tumour Suppressor Protein ◽  
Dependent Modification

Sensing of ambient dioxygen levels and appropriate feedback mechanisms are essential processes for all multicellular organisms. In animals, moderate hypoxia causes an increase in the transcription levels of specific genes, including those encoding vascular endothelial growth factor and erythropoietin. The hypoxic response is mediated by hypoxia-inducible factor (HIF), an αβ heterodimeric transcription factor in which both the HIF subunits are members of the basic helix–loop–helix PAS (PER-ARNT-SIM) domain family. Under hypoxic conditions, levels of HIFα rise, allowing dimerization with HIFβ and initiating transcriptional activation. Two types of dioxygen-dependent modification to HIFα have been identified, both of which inhibit the transcriptional response. Firstly, HIFα undergoes trans-4-hydroxylation at two conserved proline residues that enable its recognition by the von Hippel-Lindau tumour-suppressor protein. Subsequent ubiquitinylation, mediated by an ubiquitin ligase complex, targets HIFα for degradation. Secondly, hydroxylation of an asparagine residue in the C-terminal transactivation domain of HIFα directly prevents its interaction with the co-activator p300. Hydroxylation of HIFα is catalysed by enzymes of the iron(II)- and 2-oxoglutarate-dependent dioxygenase family. In humans, three prolyl hydroxylase isoenzymes (PHD1–3) and an asparagine hydroxylase [factor inhibiting HIF (FIH)] have been identified. The role of 2-oxoglutarate oxygenases in the hypoxic and other signalling pathways is discussed.

scholarly journals Metabolic Regulation of Hypoxia-Inducible Factors in Hypothalamus

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan Du ◽  
Yugang Zhang ◽  
Canjun Zhu ◽  
Hong Chen ◽  
Jia Sun
Keyword(s):  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Central Regulation ◽  
Hypoxic Conditions ◽  
Regulation Of Metabolism ◽  
Single Effect ◽  
Single Part ◽  
Main Influence

The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system’s response to glucose, inflammation, and hormones’ main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.

The role of von Hippel-Lindau tumor suppressor protein and hypoxia in renal clear cell carcinoma

2004 ◽  
Vol 287 (1) ◽  
pp. F1-F6 ◽  
Author(s):  
Roxana I. Sufan ◽  
Michael A. S. Jewett ◽  
Michael Ohh
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Renal Clear Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Vhl Protein

The majority of kidney cancers are caused by the mutation of the von Hippel-Lindau ( VHL) tumor suppressor gene. VHL protein (pVHL) is part of an E3 ubiquitin ligase complex called VEC that is composed of elongin B, elongin C, cullin 2, NEDD8, and Rbx1. VEC targets a hypoxia-inducible factor (HIF) transcription factor for ubiquitin-mediated destruction selectively in the presence of oxygen. In the absence of wild-type pVHL, as in VHL patients or in the majority of sporadic clear cell renal cell carcinomas, HIF-responsive genes are inappropriately activated even under normoxia. Recent insights into the molecular mechanisms regulating the function of pVHL, and thereby HIF, in the context of kidney cancer are the focus of this review.

scholarly journals Role of microRNAs in Obesity-Related Kidney Disease

2021 ◽  
Vol 22 (21) ◽  
pp. 11416
Author(s):  
Maite Caus ◽  
Àuria Eritja ◽  
Milica Bozic
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Significant Risk ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Rna Molecules ◽  
Small Noncoding Rna ◽  
Post Transcriptional Regulation

Obesity is a major global health problem and is associated with a significant risk of renal function decline. Obesity-related nephropathy, as one of the complications of obesity, is characterized by a structural and functional damage of the kidney and represents one of the important contributors to the morbidity and mortality worldwide. Despite increasing data linking hyperlipidemia and lipotoxicity to kidney injury, the apprehension of molecular mechanisms leading to a development of kidney damage is scarce. MicroRNAs (miRNAs) are endogenously produced small noncoding RNA molecules with an important function in post-transcriptional regulation of gene expression. miRNAs have been demonstrated to be important regulators of a vast array of physiological and pathological processes in many organs, kidney being one of them. In this review, we present an overview of miRNAs, focusing on their functional role in the pathogenesis of obesity-associated renal pathologies. We explain novel findings regarding miRNA-mediated signaling in obesity-related nephropathies and highlight advantages and future perspectives of the therapeutic application of miRNAs in renal diseases.

scholarly journals Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E8 ◽  
Author(s):  
Matthew Womeldorff ◽  
David Gillespie ◽  
Randy L. Jensen
Keyword(s):  
Cellular Response ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Poor Patient ◽  
Growth Development ◽  
The Relationship ◽  
Insight Into ◽  
Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

scholarly journals Long noncoding RNA: a dazzling dancer in tumor immune microenvironment

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Yalu Zhang ◽  
Qiaofei Liu ◽  
Quan Liao
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Noncoding Rnas ◽  
Pathological Process ◽  
Cellular Functions ◽  
Immune Microenvironment ◽  
Protein Coding ◽  
Functional Roles ◽  
Tumor Immune Microenvironment

Abstract Long noncoding RNAs (lncRNAs) are a class of endogenous, non-protein coding RNAs that are highly linked to various cellular functions and pathological process. Emerging evidence indicates that lncRNAs participate in crosstalk between tumor and stroma, and reprogramming of tumor immune microenvironment (TIME). TIME possesses distinct populations of myeloid cells and lymphocytes to influence the immune escape of cancer, the response to immunotherapy, and the survival of patients. However, hitherto, a comprehensive review aiming at relationship between lncRNAs and TIME is missing. In this review, we focus on the functional roles and molecular mechanisms of lncRNAs within the TIME. Furthermore, we discussed the potential immunotherapeutic strategies based on lncRNAs and their limitations.

scholarly journals Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma

2018 ◽  
Vol 45 (3) ◽  
pp. 1191-1204 ◽  
Author(s):  
JingJing Wu ◽  
Swei Sunny Hann
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Functional Characterization ◽  
Clinical Information ◽  
Stem Cell Differentiation ◽  
Cancer Prognosis ◽  
Protein Coding ◽  
Rna Molecules ◽  
Gene Therapies ◽  
Non Coding Rnas

Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx and occurring at high frequency in South-eastern Asia and North Africa. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules and key regulators of developmental, physiological, and pathological processes in humans. Emerging studies have shown that lncRNAs play critical roles in tumorgenicity and cancer prognosis. With the development of deep sequencing analyses, an extensive amount of functional lncRNAs have been discovered in nasopharyngeal carcinoma tissues and cell lines. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of NPC are not fully understood. In this review, we briefly illustrate the concept, identification, functional characterization, and summarize recent advancements of biological functions of lncRNAs with heterogeneous mechanistic characterization and their involvement in NPC. Then, we describe individual lncRNAs that have been associated with tumorgenesis, growth, invasion, cancer stem cell differentiation, metastasis, drug resistance and discuss the strategies of their therapeutic manipulation in NPC. We also review the emerging insights into the role of lncRNAs and their potential as biomarkers and therapeutic targets for novel treatment paradigms. Finally, we highlight the up-to-date of clinical information involving lncRNAs and future directions in the linking lncRNAs to potential gene therapies, and how modifications of lncRNAs can be exploited for prevention and treatment of NPC.

Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling

2007 ◽  
Vol 97 (05) ◽  
pp. 774-787 ◽  
Author(s):  
Norbert Weissmann ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
Frank Rose ◽  
Jörg Hänze
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Ischemic Disease ◽  
Hypoxic Conditions ◽  
Concomitant Reduction ◽  
Adaptive Processes

SummaryHypoxia-inducible factor (HIF) is an oxygen-dependent transcription factor that activates a diverse set of target genes, the products of which are involved in adaptive processes to hypoxia. Employing genetic manipulation of HIF expression, in-vivo and cellular studies have focused on HIF as a crucial factor affecting hypoxia-induced vascular remodeling.Vascular remodeling comprises processes which establish and improve blood vessel supply such as vasculogenesis, angiogenesis and arteriogenesis. These processes are observed during ontogenesis, tumor progression, ischemic disease or physical training. Furthermore, under hypoxic conditions, a pulmonary-specific type of vascular remodeling called pulmonary arterial remodeling occurs that is characterized by thickening of the vessel wall with a concomitant reduction in the vessel lumen area, thereby limiting blood flow.This response results in pulmonary hypertension with right ventricular hypertrophy, a lethal disease. In this review, we summarize and discuss mechanisms by which HIF interferes with the different vascular remodeling processes.

scholarly journals Identification of Long Noncoding RNA Associated ceRNA Networks in Rosacea

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Lian Wang ◽  
Ruifeng Lu ◽  
Yujia Wang ◽  
Xiaoyun Wang ◽  
Dan Hao ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Control Group ◽  
Group 13 ◽  
Regulatory Processes ◽  
Coexpression Networks

Rosacea is a chronic and relapsing inflammatory cutaneous disorder with highly variable prevalence worldwide that adversely affects the health of patients and their quality of life. However, the molecular characterization of each rosacea subtype is still unclear. Furthermore, little is known about the role of long noncoding RNAs (lncRNAs) in the pathogenesis or regulatory processes of this disorder. In the current study, we established lncRNA-mRNA coexpression networks for three rosacea subtypes (erythematotelangiectatic, papulopustular, and phymatous) and performed their functional enrichment analyses using Gene Onotology, KEGG, GSEA, and WGCNA. Compared to the control group, 13 differentially expressed lncRNAs and 525 differentially expressed mRNAs were identified in the three rosacea subtypes. The differentially expressed genes identified were enriched in four signaling pathways and the GO terms found were associated with leukocyte migration. In addition, we found nine differentially expressed lncRNAs in all three rosacea subtype-related networks, including NEAT1 and HOTAIR, which may play important roles in the pathology of rosacea. Our study provided novel insights into lncRNA-mRNA coexpression networks to discover the molecular mechanisms involved in rosacea development that can be used as future targets of rosacea diagnosis, prevention, and treatment.

Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression

2011 ◽  
Vol 300 (6) ◽  
pp. H2169-H2176 ◽  
Author(s):  
Yan Xue ◽  
Nan-Lin Li ◽  
Jing-Yue Yang ◽  
Yan Chen ◽  
Lu-Lu Yang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Suppressor ◽  
Active Form ◽  
Hypoxia Inducible Factor ◽  
Pi3k Pathway ◽  
Rho Proteins ◽  
Phosphatidylinositol 3 Kinase ◽  
Von Hippel Lindau ◽  
Phosphatidylinositol 3

We have previously demonstrated the roles of RhoA, Rac1, and Cdc42 in hypoxia-driven angiogenesis. However, the role of oncogenes in hypoxia signaling is poorly understood. Given the importance of Rho proteins in the hypoxic response, we hypothesized that Rho family members could act as mediators of hypoxic signal transduction. We investigated the cross-talk between hypoxia and oncogene-driven signal transduction pathways and explored the role of Rac1 on hypoxia-induced hypoxia-inducible factor (HIF)-1α and VEGF expression. Since the phosphatidylinositol 3′-kinase (PI3K) pathway is involved in signal transduction of many oncogenes, we explored the role of PI3K on Rac1-mediated expression of HIF-1α and VEGF in hypoxia. We showed that LY-294002, a PI3K inhibitor, suppressed HIF-1α and VEGF induction under hypoxic conditions by up to 50%. Activation of Rac1 resulted in an upregulation of hypoxia-induced HIF-1α expression, which was blocked by LY-294002. These data suggested that Rac1 is an intermediate in the PI3K-mediated induction of HIF-1α. Interestingly, there was a significant downregulation of the tumor suppressor genes p53 and von Hippel-Lindau tumor suppressor (VHL) in cells expressing a constitutively active form of Rac1. Rac1-mediated inhibition of p53 and VHL could therefore be implicated in the upregulation of HIF-1α expression.

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