Hypoxia-inducible factor 1-alpha is a driving mechanism linking chronic obstructive pulmonary disease to lung cancer

Xu, Yuan-rui; Wang, An-long; Li, Yaqing

doi:10.3389/fonc.2022.984525

Cited by 4 publications

(3 citation statements)

References 120 publications

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“…Several studies have investigated the relationship between HIF-1α and COPD and found that HIF-1α expression is increased in COPD patients, resulting in upregulated expression of inflammatory factors, which is associated with disease severity ( 23 , 24 , 32 ). Furthermore, the HIF-1α signaling pathway has been shown to be an important signaling pathway that drives COPD progression to lung cancer ( 33 ). The present study investigated the role of miR-186-5p in regulating HIF-1α expression and its impact on COPD inflammation.…”

Section: Discussionmentioning

confidence: 99%

miR‑186‑5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF‑1α

Fu,

Zhao,

Chen

et al. 2024

Mol Med Rep

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Chronic obstructive pulmonary disorder (COPD) is a chronic respiratory disease that is a major cause of morbidity and mortality worldwide. Previous studies have shown that miR-186-5p expression is significantly increased in COPD and is involved in multiple physiological and pathological processes. However, the role of miRNA-186-5p in the inflammatory response of COPD remains unclear. In this study, an in vitro model of COPD was established using lipopolysaccharide (LPS)-induced human bronchial epithelial cells (BEAS-2B). CCK-8 assays, flow cytometry, and a Muse cell analyzer were used to determine cell viability, cell cycle distribution, and apoptosis, respectively. The production of TNF-α and IL-6 were measured by ELISA. Reverse-transcription-quantitative PCR and western blotting were used to analyze mRNA and protein expression levels. The targeting relation between miR-186-5p and HIF-1α was discovered using dual-luciferase reporter assays. The results showed that transfection of miR-186-5p inhibitor inhibited cell proliferation and promoted cell apoptosis in the LPS-induced BEAS-2B cells. Inhibition of miR-186-5p markedly increased the levels of TNF-α and IL-6 . miR-186-5p directly targeted and negatively regulated HIF-1α expression. In addition, inhibition of miR-186-5p increased the expression of the NF-κB pathway protein p-p65. In conclusion, it was found that inhibiting miR-186-5p may improve inflammation of COPD through HIF-1α in LPS-induced BEAS-2B cells, possibly by regulating NF-κB signaling. These findings provide a novel potential avenue for the clinical management of COPD. Future research is required to determine the mechanism of the interaction between miR-186-5p and HIF-1α in COPD.

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Section: Discussionmentioning

confidence: 99%

miR‑186‑5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF‑1α

Fu,

Zhao,

Chen

et al. 2024

Mol Med Rep

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“…A description of most remarkable events occurring during the aetiopathogenesis of COPD and that may be of interest for the oxidative pathways are described in Figure 2 and Figure 3 commented on. Each individual event is in accordance with the most recent literature as follows: (a) Aging: the gradual decline attributed to physiological lung aging is accompanied by various host and environmental factors throughout life [ 55 ]; (b) Gene × Environment: stems from interactions between genetic (G) and environmental (E) factors across an individual’s lifespan (T) (referred to as GETomics), which can lead to lung damage or disrupt their normal developmental and aging processes [ 9 ]; (c) Comorbidity: recent findings indicate that the number of comorbidities, as assessed by the CIRS score, among patients with COPD influences the risk of moderate-to-severe exacerbations and correlates with the severity of respiratory symptoms and lung function [ 33 ]; (d) Hypoxia: Significantly contributes to COPD, increasing HIF-1α expression in hypoxic tissues and the serum inducing NF-κB expression [ 56 ]. Hypoxic environments favor the accumulation of ROS and increased oxidative stress [ 57 ]; (e) Virus infection: cigarette smoke is a well-known contributing factor to the onset and exacerbation of infectious diseases caused by viruses, such as SARS-CoV-2 [ 21 ] and influenza virus [ 22 ]; (f) Immunological changes: Current smokers have an increased inflammatory response following bacterial stimulation.…”

Section: Discussionmentioning

confidence: 99%

Effect of Cigarette Smoking on Clinical and Molecular Endpoints in COPD Patients

Russo,

Milani,

De Iure

et al. 2024

IJMS

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Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; p < 0.001), Platelets/Lymphocytes ratio (p < 0.001), systemic immune inflammation (p < 0.05), and DNA damage (p < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers (p < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections).

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“…One of the mechanisms by which glycolysis influences lung cancer is through its effect on hypoxia-inducible factor 1 (HIF-1), which is activated by low oxygen levels and high glycolytic activity in tumor cells, leading to increased expression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and glucose transporters (GLUTs). HIF-1 also suppresses the anti-tumor immune response by inducing Tregs, myeloid-derived suppressor cells (MDSCs), and immunosuppressive cytokines such as IL-10 and transforming growth factor-beta (TGF-beta) ( Corzo et al, 2010 ; Xu Y. R. et al, 2022 ). Therefore, targeting glycolysis or its pathway regulators may enhance anti-tumor immunity by reducing immunosuppression or increasing the immunogenicity of cancer cells ( Vaupel and Multhoff, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Intratumor microbiome derived glycolysis-lactate signatures depicts immune heterogeneity in lung adenocarcinoma by integration of microbiomic, transcriptomic, proteomic and single-cell data

Deng,

Chen,

Luo

et al. 2023

Front. Microbiol.

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IntroductionMicrobiome plays roles in lung adenocarcinoma (LUAD) development and anti-tumor treatment efficacy. Aberrant glycolysis in tumor might promote lactate production that alter tumor microenvironment, affecting microbiome, cancer cells and immune cells. We aimed to construct intratumor microbiome score to predict prognosis of LUAD patients and thoroughly investigate glycolysis and lactate signature’s association with LUAD immune cell infiltration.MethodsThe Cancer Genome Atlas-LUAD (TCGA-LUAD) microbiome data was downloaded from cBioPortal and analyzed to examine its association with overall survival to create a prognostic scoring model. Gene Set Enrichment Analysis (GSEA) was used to find each group’s major mechanisms involved. Our study then investigated the glycolysis and lactate pattern in LUAD patients based on 19 genes, which were correlated with the tumor microenvironment (TME) phenotypes and immunotherapy outcomes. We developed a glycolysis-lactate risk score and signature to accurately predict TME phenotypes, prognosis, and response to immunotherapy.ResultsUsing the univariate Cox regression analysis, the abundance of 38 genera were identified with prognostic values and a lung-resident microbial score (LMS) was then developed from the TCGA-LUAD-microbiome dataset. Glycolysis hallmark pathway was significantly enriched in high-LMS group and three distinct glycolysis-lactate patterns were generated. Patients in Cluster1 exhibited unfavorable outcomes and might be insensitive to immunotherapy. Glycolysis-lactate score was constructed for predicting prognosis with high accuracy and validated in external cohorts. Gene signature was developed and this signature was elevated in epithelial cells especially in tumor mass on single-cell level. Finally, we found that the glycolysis-lactate signature levels were consistent with the malignancy of histological subtypes.DiscussionOur study demonstrated that an 18-microbe prognostic score and a 19-gene glycolysis-lactate signature for predicting prognosis of LUAD patients. Our LMS, glycolysis-lactate score and glycolysis-lactate signature have potential roles in precision therapy of LUAD patients.

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Hypoxia-inducible factor 1-alpha is a driving mechanism linking chronic obstructive pulmonary disease to lung cancer

Cited by 4 publications

References 120 publications

miR‑186‑5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF‑1α

miR‑186‑5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF‑1α

Effect of Cigarette Smoking on Clinical and Molecular Endpoints in COPD Patients

Intratumor microbiome derived glycolysis-lactate signatures depicts immune heterogeneity in lung adenocarcinoma by integration of microbiomic, transcriptomic, proteomic and single-cell data

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