Normal Lung Tissue Research Articles

IGF2BP3/CTCF Axis-Dependent NT5DC2 Promotes M2 Macrophage Polarization to Enhance the Malignant Progression of Lung Squamous Cell Carcinomas.

Lung squamous cell carcinoma (LUSC) is a type of lung cancer that develops in the squamous cells. It is known to be promoted by the activation of various signaling pathways and the dysregulation of key regulatory molecules. One such molecule, 5'-nucleotidase domain containing 2 (NT5DC2), has been identified as a critical regulator in various cancers including lung cancer. However, there are no data regarding its role in LUSC. The mRNA expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), CCCTC-binding factor (CTCF), and NT5DC2 was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR), whereas their protein expression was assessed using a western blotting assay. Cell proliferation was determined using a cell counting kit-8 (CCK-8) assay. Cell apoptosis, CD11b expression, and CD206 expression were analyzed using flow cytometry. Tube formation was assessed through a tube formation assay. Glucose consumption, lactate production, and ATP levels were measured using colorimetric methods. The effect of NT5DC2 on the malignant progression of LUSC cells was analyzed using a xenograft mouse model assay. The levels of transforming growth factor-beta 1 (TGF-β1) and interleukin-10 (IL-10) were detected using enzyme-linked immunosorbent assays. The associations among IGF2BP3, CTCF and NT5DC2 were identified using dual-luciferase reporter assay, RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. The expression of NT5DC2 was found to be upregulated in LUSC tissues and cells when compared with normal lung tissues and normal human bronchial epithelial cells. Silencing of NT5DC2 inhibited LUSC cell proliferation, tube formation, glycolysis, M2 macrophage polarization, and tumor formation while inducing cell apoptosis. In addition, CTCF was found to transcriptionally activate NT5DC2 in LUSC cells. IGF2BP3 stabilized the mRNA expression of CTCF through m6A methylation. Further, overexpression of CTCF or NT5DC2 attenuated the effects of IGF2BP3 silencing in both NCI-520 and SK-MES-1 cells. The IGF2BP3/CTCF axis-dependent NT5DC2 promotes M2 macrophage polarization, thereby enhancing the malignant progression of LUSC. This study was the first to reveal the role of NT5DC2 in LUSC and the underlying mechanism. The result suggests that targeting the IGF2BP3/CTCF/NT5DC2 axis may have clinical significance in the treatment of LUSC.

FSP1 Acts in Parallel with GPX4 to Inhibit Ferroptosis in COPD.

Glutathione peroxidase 4 (GPX4) has recently been reported to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Ferroptosis suppressor protein-1 (FSP1) is a protein that defends against ferroptosis in parallel with GPX4, but its role in the pathogenesis of COPD remains unexplored, and further research is needed. Normal and COPD lung tissues were obtained from lobectomy and lung transplant specimens, respectively. FSP1-overexpressing mice were established by monthly transfection with AAV9-FSP1 through modified intranasal administration. The expression of FSP1, GPX4, and prostaglandin-endoperoxide synthase 2 (PTGS2) was measured by Western blotting, immunohistochemistry and other methods. The correlation between FSP1 and ferroptosis and the role of FSP1 in COPD were explored by screening the expression of ferroptosis-related genes in a COPD cell model after the inhibition and overexpression of FSP1. We then explored the underlying mechanism of low FSP1 expression in patients with COPD in vitro by methylated RNA immunoprecipitation (MeRIP)-qPCR. We found that cigarette smoke exposure can lead to an increase in lipid peroxide production and ultimately ferroptosis, which is negatively regulated by FSP1 activity. FSP1 overexpression can prevent ferroptosis and alleviate emphysema. Next, we found that decreased FSP1 expression was caused by increased m6A modification of FSP1 mRNA. Moreover, the level of FSP1 decreased in a YTHDF2-dependent manner. These results indicate that METTL3-induced FSP1 mRNA methylation leading to low FSP1 expression is a potential therapeutic target for COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ERH is a prognostic biomarker associated with immune cell infiltration in lung cancer

Introduction The enhancer of rudimentary homolog (ERH) is significant in cancers, but its role in lung cancer is understudied. We divided lung cancer patients into high and low ERH expression groups based on tumor tissue levels. Methods Using the log-rank test, we analyzed the correlation between ERH expression and patient prognosis. The effects of high ERH expression on lung cancer cell proliferation, migration, and invasion were assessed using CCK8, EDU, transwell, and wound healing assays. Results ERH expression was significantly higher in cancerous versus normal lung tissue (p < 0.05), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Patients with high ERH expression had worse overall survival (HR = 1.37, p = 2.5 × 10−7) and first progression survival (HR = 1.38, p = 0.00065) in lung cancer. However, while high ERH expression predicts an unfavorable prognosis in LUAD, it does not hold true for LUSC. Furthermore, knockdown of ERH inhibited lung cancer cell proliferation, migration, and invasion. ERH expression was linked to immune cell infiltration. High ERH expression in LUAD and LUSC samples correlated with higher CD8 T cell, T cells CD4 memory activated, and M1 macrophages abundance, while low ERH expression correlated with higher T cells CD4 memory resting abundance. Conclusion Upregulation of ERH in lung cancer tissue is associated with poor prognosis and immune cell infiltration.

Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

Optimization, characterization and biosafety of carotenoids produced from whey using Micrococcus luteus

This study aimed to optimize the production of carotenoid pigments from Micrococcus luteus (ATCC 9341) through the statistical screening of media components and the characterization of antimicrobial, antioxidant, cytogenetic and cytotoxic activities. A BOX-Behnken design was used to assess the effects of whey concentration, inoculum size, pH, temperature, and agitation speed on carotenoid yield. The optimum combination increased production to 2.19 g/L, with a productivity of 0.045 g L-1 h−1 and a productivity yield of 0.644 g/g, as confirmed by an observed carotene production of 2.19 g/L. The final response surface model fitting the data had an R2 of 0.9461. High-performance liquid chromatography (HPLC) analysis identified 12 carotenoid pigment compounds produced by M. luteus. The extracts displayed moderate antimicrobial efficacy against Gram-positive bacteria such as Bacillus cereus (ATCC 11778), Staphylococcus aureus (ATCC 6538), and E. faecalis (ATCC 19433), with inhibition zone diameters (IZD) of 29.0, 14.0, and 37.0 mm, respectively, at 1000 μg/mL. However, its effectiveness against Gram-negative bacteria is limited. In comparison, tetracycline exhibited greater antimicrobial potency. The IC50 value of carotenoids was used to indicate the antioxidant activity. IC50 value from the DPPH assay was 152.80 mg/100mL. An IC50 cytotoxicity value greater than 300 μg/mL was found against normal mouse liver cells, with over 68% cell viability even at 300 μg/mL, indicating low toxicity. Histological structure studies revealed normal myocardial muscle tissue, lung tissue, and kidney tissue sections, whereas liver tissue sections revealed ballooning degeneration of hepatocytes and disorganization of hepatic cords. Cytogenetic parameters revealed that the carotene treatment group had a mitotic index (70%) lower than that of the control but higher than that of the positive control, mitomycin, and did not substantially increase numerical (1.2%) or structural aberrations compared with those of the control, suggesting a lack of genotoxic effects under the experimental conditions. In conclusion, optimized culture conditions enhanced carotenoid yields from M. luteus, and the extracts displayed promising bioactivity as moderate antibiotics against certain gram-positive bacteria and as antioxidants. The high IC50 values demonstrate biosafety. Overall, this bioprocess for enhanced carotenoid production coupled with bioactivity profiling and low cytotoxicity support the application of M. luteus carotenoids.

STAT3/p-STAT3 expression is correlated with clinicopathological characteristics and prognosis in non-small cell lung cancer.

Signal transducer and activator of transcription factor 3 (STAT3)/phosphorylated STAT3 (p-STAT) play a critical role in tumorigenesis, however, there is limited information on its prognostic value in non-small cell lung cancer (NSCLC). To address this question, 239 lung cancer and 71 normal lung tissue samples were obtained in this study. Immunohistochemistry was applied to detect STAT3/p-STAT3 expression. Pearson's Chi-squared test and the Kaplan-Meier method were conducted to evaluate associations with patients' clinical characteristics and survival. According to our results, STAT3/p-STAT3 was significantly upregulated in lung cancer tissue (p<0.001). Moreover, p-STAT3 expression was significantly correlated with age (p=0.046) and pathological types (p=0.037). In survival analysis, STAT3 positivity was negatively associated with survival in patients older than 60 years (p=0.043) but failed to be an independent prognostic factor in multivariate analysis (p=0.083). Therefore, STAT3/p-STAT3 may serve as a critical biomarker in NSCLC.

Dosimetric comparison of gamma knife and linear accelerator (VMAT and IMRT) plans of SBRT of Lung tumours

This study evaluates dosimetric differences in Stereotactic Body Radiation Therapy (SBRT) for lung tumors using plans of Gamma Knife, and Volumetric Modulated Arc Therapy (VMAT), Intensity-Modulated Radiation Therapy (IMRT) plans based on Linear Accelerator, aiming to inform the reader of appropriate treatment strategy selection. Ten patients with 23 lung tumor lesions treated with SBRT at Zhongshan Hospital of Dalian University were analyzed. Plans of Gamma Knife, and VMAT, IMRT plans based on Linear Accelerator were created for each lesion, totaling 18 plans per type. Lesions were treated with 30–50 Gy in 5–10 fractions. Dosimetric parameters, including gradient index (GI), heterogeneity index (HI), conformity index (CI), and doses to the plan target volumes (PTVs), the gross tumor volumes (GTVs) and organs at risk (OARs) were compared. Plans of Gamma Knife showed superior HI and GI, higher PTV and GTV doses, and reduced doses to the ipsilateral and contralateral lungs, esophagus, spinal cord, and heart compared to VMAT and IMRT plans (p < 0.05). However, Plans of Gamma Knife required longer delivery times. When comparing VMAT and IMRT plans, VMAT plans had shorter delivery times than IMRT plans, but required more monitor units (MUs). Additionally, IMRT plans delivered a lower mean dose to the ipsilateral lung compared to VMAT plans. Gamma Knife SBRT plans achieves steeper dose falloff and minimizes radiation to normal lung tissue compared to VMAT and IMRT plans, but with longer delivery times. VMAT and IMRT plans displayed similar dose distributions for lung SBRT.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival.

T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported. We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants. Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood. Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

FAS gene expression, prognostic significance and molecular interactions in lung cancer.

FAS has been implicated in the development of various cancers, but its involvement in lung cancer has not been systematically characterized. In this study, we performed data mining in online tumor databases to investigate the expression, methylation, alterations, protein interactions, co-expression and prognostic significance of FAS in lung cancer. The expression, prognostic significance and molecular interactions of FAS in lung cancer was mined and analyzed using GENT2, GEPIA2, UALCAN, cBioPortal, STRING, GeneMANIA, UCSC Xena, Enrichr, and OSluca databases. FAS expression was subsequently investigated at the protein level in samples from 578 lung cancer patients to understand its protein-level expression. In vitro validation of FAS gene expression was performed on H1299, H1993, A549 and HBE cell lines. We found that the expression of FAS was significantly downregulated in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) compared to normal lung tissue. In addition, we observed a higher level of FAS promoter methylation in LUSC tissue than in normal tissue. FAS alterations were rare (1.9%) in lung cancer samples, with deep deletions being more common than missense mutations, which occurred mainly in the TNFR-like cysteine-rich domain and the death domain. We also identified a list of proteins interacting with FAS and genes co-expressed with FAS, with LUAD having 11 co-expressed genes and LUSC having 90 co-expressed genes. Our results also showed that FAS expression has limited prognostic significance (HR=1.302, 95% CI=0.935-1.139, P=0.530). Protein level investigation revealed that FAS expression varied among individuals, with nTPM values ranging from 5.2 to 67.2. This study provides valuable insights into the involvements and characteristics of FAS in lung cancer. Further studies are needed to investigate the clinical significance of FAS alterations in lung cancer and to explore the potential of targeting FAS for therapeutic intervention.

The In vitro evaluation of in silico-designed synthetic peptides AKVUAM-1 and AKVUAM-2 on human lung fibroblast cell line MRC5 and Mycobacterium tuberculosis isolates

Tuberculosis is a major global health problem caused by Mycobacterium tuberculosis and the increase in drug resistance is driving the need for new treatments. Today, various approaches are being applied in the development of drugs for the treatment of tuberculosis. Computer-aided drug design (CADD) enables the prediction of pharmacological efficacy for potential drug molecules during the design process. Thus, new therapeutic compounds can be developed that are more potent, less toxic and have fewer side effects than existing drugs. In this study, we investigated the in vitro activities of AKVUAM-1 and AKVUAM-2 synthetic peptides designed in silico by computer-aided drug design method to inhibit the interaction between M. tuberculosis outer membrane protein Cpn T and macrophage surface receptor CR-1 and Surfactant D protein. Notably, these synthetic peptides do not show cytotoxic effect on normal lung tissue and do not kill M. tuberculosis directly. The MIC values for AKVUAM-1 were higher than 512 μg/ml for all bacterial strains except IST-16 strain (128 μg/ml). According to our results, AKVUAM-1 and AKVUAM-2 synthetic peptides have the potential to be successful candidates for investigating their potential to block macrophage entry of bacilli as targeted.

SULF1 expression is increased and promotes fibrosis through the TGF-β1/SMAD pathway in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor prognosis, the exact pathogenic mechanisms remain elusive. Currently, effective therapeutic targets and treatment methods for this disease are still lacking. This study tried to explore the pathogenic mechanisms of IPF. We found elevated expression of SULF1 in lung tissues of IPF patients compared to normal control lung tissues. SULF1 is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans, playing a critical role in biological regulation. However, the effect of SULF1 in pulmonary fibrosis remains incompletely understood. Our study aimed to investigate the impact and mechanisms of SULF1 in fibrosis.MethodsWe collected lung specimens from IPF patients for transcriptome sequencing. Validation of SULF1 expression in IPF patients was performed using Western blotting and RT-qPCR on lung tissues. ELISA experiments were employed to detect SULF1 concentrations in IPF patient plasma and TGF-β1 levels in cell culture supernatants. We used lentiviral delivery of SULF1 shRNA to knock down SULF1 in HFL1 cells, evaluating its effects on fibroblast secretion, activation, proliferation, migration, and invasion capabilities. Furthermore, we employed Co-Immunoprecipitation (Co-IP) to investigate the regulatory mechanisms involved.ResultsThrough bioinformatic analysis of IPF transcriptomic sequencing data (HTIPF) and datasets GSE24206, and GSE53845, we identified SULF1 may potentially play a crucial role in IPF. Subsequently, we verified that SULF1 was upregulated in IPF and predominantly increased in fibroblasts. Furthermore, SULF1 expression was induced in HFL1 cells following exposure to TGF-β1. Knockdown of SULF1 suppressed fibroblast secretion, activation, proliferation, migration, and invasion under both TGF-β1-driven and non-TGF-β1-driven conditions. We found that SULF1 catalyzes the release of TGF-β1 bound to TGFβRIII, thereby activating the TGF-β1/SMAD pathway to promote fibrosis. Additionally, TGF-β1 induces SULF1 expression through the TGF-β1/SMAD pathway, suggesting a potential positive feedback loop between SULF1 and the TGF-β1/SMAD pathway.ConclusionsOur findings reveal that SULF1 promotes fibrosis through the TGF-β1/SMAD pathway in pulmonary fibrosis. Targeting SULF1 may offer a promising therapeutic strategy against IPF.

Simultaneous unilateral thoracoscopic resection of bilateral pulmonary sequestration

BackgroundIntra-lobar (ILS) and extra-lobar lung (ELS) sequestrations represent rare congenital lung malformations. Despite their benign nature, the lesions pose risks such as recurrent pulmonary infections, hemoptysis, congestive heart failure, and tumor development. Pulmonary sequestration (PS) typically manifests in two forms, ILS and ELS, with bilateral occurrence being exceptionally rare and mostly requiring bilateral thoracic surgery.Case presentationA 9-year-old child, who initially presented with bilateral lung lesions without respiratory symptoms, was diagnosed with PS following a chest computed tomography scan. The surgical approach was determined based on the absence of inflammation and the clear demarcation of the lesions from normal lung tissue, highlighted by a unique tissue connection between the ILS and ELS across the chest cavities. We used a novel method wherein the left ELS was successfully pulled into the right chest cavity and both sequestrations were concurrently resected. Postoperative recovery was smooth, with no complications or residual lesions.ConclusionsOur findings highlight the importance of thorough preoperative planning with enhanced computed tomography. Simultaneous unilateral thoracoscopic surgery can be a viable, less invasive option for treating bilateral PS, offering benefits such as reduced recovery time and better cosmetic outcomes.

GTSE1-driven ZEB1 stabilization promotes pulmonary fibrosis through the epithelial-to-mesenchymal transition

G2 and S phase-expressed protein 1 (GTSE1) has been implicated in the development of pulmonary fibrosis (PF); however, its biological function, molecular mechanism, and potential clinical implications remain unknown. Here, we explored the genomic data of patients with idiopathic PF (IPF) and found that GTSE1 expression is elevated in their lung tissues, but rarely expressed in normal lung tissues. Thus, we explored the biological role and downstream events of GTSE1 using IPF patient tissues and PF mouse models. The comprehensive bioinformatics analyses suggested that the increase of GTSE1 in IPF is linked to the enhanced gene signature for the epithelial-to-mesenchymal transition (EMT), leading us to investigate the potential interaction between GTSE1 and EMT transcription factors. GTSE1 preferentially binds to the less stable form of zinc-finger E-box-binding homeobox 1 (ZEB1), the unphosphorylated form at Ser585, inhibiting ZEB1 degradation. Consistently, the ZEB1 protein level in IPF patient and PF mouse tissues correlates with the GTSE1 protein level and the amount of collagen accumulation, representing fibrosis severity. Collectively, our findings highlight the GTSE1–ZEB1 axis as a novel driver of the pathological EMT characteristic during PF development and progression, supporting further investigation into GTSE1-targeting approaches for PF treatment.

Potentially functional variants of PARK7 and DDR2 in ferroptosis-related genes predict survival of non-small cell lung cancer patients.

Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (ptrend = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels.

MiR-2110 Affects the Biological Behaviors of Lung Adenocarcinoma by Regulating CDT1

To investigate the effect of miR-2110 on the biological behaviors, such as cell proliferation, apoptosis, and metastasis, of lung adenocarcinoma (LUAD) cells by means of cell and animal experiments. Bioinformatics websites, including ENCORI, TargetScan, miRTarBase, and Tarbase, were used to analyze the changes in the expression of miR-2110 in LUAD samples and to predict miR-2110 target. LUAD tissue samples and cells were collected and the changes in the expression of miR-2110 were verified through PCR technology. CCK-8 assay, clonogenic assay, Transwell assay, and flow cytometry were conducted to analyze alterations in the functions of LUAD cells. In addition, 10 BALB/c female nude mice aged 6 to 8 weeks were randomly divided into 2 groups, and the effect of miR-2110 on LUAD was investigated by in vivo experiments. miR-2110 was significantly decreased in LUAD tissues and cells compared with the normal lung tissues. miR-2110 overexpression inhibited the proliferation and metastasis of LUAD cells and promoted the apoptosis of tumor cells (P<0.05). Bioinformatics prediction and dual luciferase reporter gene assay results confirmed that miR-2110 could target and bind to CDT1. In addition, overexpression of CDT1 gene reversed the proliferation, metastasis, and apoptosis of miR-2110 compared with the miR-2110 overexpression group (P<0.05). Nude mice in vivo experiments showed that miR-2110 overexpression significantly decreased the expression of Ki67, a tumor proliferation index, and vimentin and MMP9, two metastasis indices, compared with the control group. miR-2110 can inhibit proliferation and metastasis of LUAD by targeting CDT1, providing a new rationale for the treatment of LUAD.

Exploring the relationship between the interleukin family and lung adenocarcinoma through Mendelian randomization and RNA sequencing analysis

BackgroundLung adenocarcinoma (LUAD) is still one of the most prevalent malignancies. Interleukin factors are closely associated with the initiation and progression of cancer. However, the relationship between interleukin factors and LUAD has not been fully elucidated. This study aimed to use Mendelian randomization (MR) and RNA sequencing (RNA-seq) analyses to identify the interleukin factors associated with the onset and progression of LUAD.MethodsExposure-related instrumental variables were selected from interleukin factor summary datasets. The LUAD summary dataset from FINGENE served as the outcome. MR and sensitivity analyses were conducted to screen for interleukin factors associated with LUAD occurrence. Transcriptome analyses revealed the role of interleukin factors in lung tissues. The results were validated through Western blotting and further confirmed with driver gene-negative patients from multiple centers. Potential mechanisms influencing LUAD occurrence and development were explored using bulk RNA-seq and single-cell RNA-seq data.ResultsMR analysis indicated that elevated plasma levels of IL6RB, IL27RA, IL22RA1, and IL16 are causally associated with increased LUAD risk, while IL18R1 and IL11RA exhibit the opposite effect. Transcriptome analyses revealed that IL11RA, IL18R1, and IL16 were downregulated in tumor tissues compared with normal lung tissue, but only higher expression of IL11RA correlated with improved prognosis in patients with LUAD from different centers and persisted even in driver-gene negative patients. The IL11RA protein level was lower in various LUAD cell lines than in human bronchial epithelial cells. The genes co-expressed with IL11RA were enriched in the Ras signaling pathway and glycosylation processes. Fibroblasts were the primary IL11RA-expressing cell population, with IL11RA+fibroblasts exhibiting a more immature state. The genes differentially expressed between IL11RA+and IL11RA- fibroblasts were involved in the PI3K-Akt/TNF signaling pathway.ConclusionAccording to the MR and transcriptome analyses, the downregulation of IL11RA was closely related to the occurrence and development of LUAD.Graphical

Clinical Significance of the Expression of Long Non-Coding RNA LINC01508 in Non-Small Cell Lung Cancer.

The expression of long non-coding RNA (lncRNA) LINC01508 was studied in tumor samples from patients with non-small cell lung cancer (NSCLC), and its clinical significance was evaluated. The expression of LINC01508 lncRNA was measured in 16 pairs of NSCLC samples and its association with clinical and morphological features of the disease and prognosis analyzed. A comparative analysis showed a significant decrease in the expression of LINC01508 in tumor lung tissue in comparison with the surrounding normal lung tissue. The informativity of the diagnostic method was tested using ROC curve analysis and calculation of the area under the curve (AUC) for LINC01508 in NSCLC patients, which showed an AUC of 0.875 (p=0.001). No significant associations of LINC01508 expression level with clinical and morphological characteristics of the disease were found. The analysis of prognostic significance showed that high expression of LINC01508 in NSCLC samples was a favorable prognostic factor. Despite the fact that the results did not reach statistical significance (p=0.107), the median survival rate for patients with low LINC01508 expression was 16 months, while for patients with high expression, it was not reached during the follow-up period. We believe that LINC01508 can be a promising independent prognostic marker for NSCLC.

Role and Therapeutic Potential of P2X7 Receptor in Lung Cancer Progression.

Lung cancer is the second malignant tumor in the world and is the most prevalent malignant tumor of the respiratory system. In lung cancer, the P2X7 receptor (P2X7R) is an important purinergic receptor. P2X7R is a class of ionotropic adenosine triphosphate (ATP)-gated receptors, which exists in many kinds of immune tissues and cells and is involved in tumorigenesis and progression. P2X7R is closely related to lung cancer and is expressed at higher levels in lung cancer than in normal lung tissue. P2X7R plays a critical regulatory function in lung cancer invasion and migration through multiple mechanisms of action and affects the proliferation and apoptosis of cancer cells in the lung. Antagonists of P2X7R can block its function, which in turn has a significant inhibitory effect on lung cancer cell development and progression. This paper details a comprehensive overview of the structure and function of P2X7R. It focuses on the impact and treatment potential of P2X7R in lung cancer invasion, migration, proliferation, and apoptosis, providing new ideas and a new basis for clinical lung cancer treatment and prognosis.

Exploring the prognosis value, immune correlation, and drug responsiveness prediction of homeobox C6 (HOXC6) in lung adenocarcinoma

BackgroundsHomeobox C6 (HOXC6) is a gene that encodes for a transcription factor involved in various cellular processes, including development and differentiation, and regulates cancer progression. However, the carcinogenesis and effect of HOXC6 in lung adenocarcinoma (LUAD) still need further investigation.MethodsThe differential HOXC6 expression levels at the mRNA and protein level were explored in multiple public datasets, including The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) dataset. Gene Expression Omnibus (GSE31210), International Cancer Genome Consortium (ICGC) datasets and the LUAD sample from Affiliated Hospital of Guangxi Medical University. We also investigated the relation between HOXC6 expression and clinicopathologic indexes. Furthermore, the correlation of immune infiltration, drug responsiveness and HOXC6 were explored.ResultsThe upregulated HOXC6 expressions at mRNA and protein levels were found in LUAD tissues compared to the normal lung tissues. Besides, the relatively shorter overall survival time, worse T and N stages, and lower immune scores were found in the high-expression HOXC6 subgroup. Notably, T cells regulatory (Tregs), Macrophages M0, and Plasma cells had the higher infiltration levels in the high-HOXC6 expression subgroup, while NK cells activated, Monocytes, Dendritic cells resting, and Mast cells resting had the lower infiltration levels. In drug sensitivity analysis, we revealed that LUAD patients with high-HOXC6 expression may be more susceptible to Camptothecin, Cytarabine, Docetaxel, Elesclomol, Rapamycin, Sorafinib, Temsirolimus, and Vorinostat.ConclusionsTaken together, there is a great potential for HOXC6 to become a prognosis biomarker and contribute to develop treatment strategies for LUAD patients. Further mechanism exploration and drug development for HOXC6 are needed.