Identification of immune biomarkers associated with basement membranes in idiopathic pulmonary fibrosis and their pan-cancer analysis

Fu, Chenkun; Chen, Lina; Cheng, Yiju; Yang, Wenting; Zhu, Huaqun; Wu, Xiao; Cai, Banruo

doi:10.3389/fgene.2023.1114601

Cited by 3 publications

References 98 publications

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Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis

Wang,

Ni,

Liu

et al. 2024

Preprint

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BackgroundPulmonary fibrosis (PF) is a shared characteristic of chronic interstitial lung diseases of mixed aetiology. Previous studies on PF highlight a pathogenic role for common and rare genetic variants. This study aimed to identify rare pathogenic variants that are enriched in distinct biological pathways and dysregulated gene expression.MethodsRare variants were identified using whole genome sequencing (WGS) from two independent PF cohorts, the PROFILE study and the Genomics England 100K (GE100KGP) cohort, with the gnomAD database as a reference. Four pathogenic variant categories were defined: loss of function variants, missense variants, protein altering variants, and protein truncating variants. Gene burden testing was performed for rare variants defined as having a minor allele frequency <0.1%. Overrepresentation analysis of gene ontology terms and gene concept network analysis were used to interpret functional pathways. Integration of publicly available transcriptomic datasets was performed using weighted gene co-expression network analysis of idiopathic pulmonary fibrosis (IPF) lung tissue compared with healthy controls.ResultsBurden testing was performed on 507 patients from the PROFILE study and 451 PF patients from GE100KGP cohort, compared with 76,156 control participants from the gnomAD database. Ninety genes containing significantly more pathogenic rare variants in cases than in controls were observed in both cohorts. Fifty-six genes included missense variants and 87 genes included protein altering variants. For missense variants,HMCN1, encoding hemicentin-1, andRGPD1, encoding a protein with a RanBD1 domain, were highly associated with PF in both PROFILE (p=5.70E-22 and p=4.48E-51, respectively) and GE100KGP cohorts (p=2.27E-24 and p=1.59E-36, respectively). 56 of 90 genes with significant burden were observed within modules correlated with disease in transcriptomic analysis, includingHMCN1andRGPD1. Enriched functional categories from genetic and transcriptomic analyses included pathways involving extracellular matrix constituents, cell adhesion properties and microtubule organisation.ConclusionsRare pathogenic variant burden testing and weighted gene co-expression network analysis of transcriptomic data provided complementary evidence for pathways regulating cytoskeletal dynamics in PF pathogenesis. Functional validation of candidates could provide novel targets for intervention strategies.

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Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis

Wang,

Ni,

Liu

et al. 2024

Preprint

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The Deubiquitinase USP22‐Stabilized COL17A1 Promotes Lung Adenocarcinoma Progression

Chen,

Du,

Wang

et al. 2024

Clinical Respiratory J

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BackgroundLung adenocarcinoma (LUAD) is a highly aggressive and rapidly fatal malignancy worldwide. Collagen XVII (COL17A1) has been implicated in various protumorigenic processes. However, the functions and mechanisms of COL17A1 in LUAD progression still remain elusive.MethodsCOL17A1 and ubiquitin‐specific protease 22 (USP22) mRNA analysis was performed by quantitative PCR, and their protein levels were detected by immunoblotting and immunohistochemistry. The functional influence was evaluated by determining cell viability, proliferation, apoptosis, invasion, migration, and ferroptosis in vitro, as well as xenograft growth in vivo. Co‐immunoprecipitation (Co‐IP) and IP experiments were used to examine the USP22/COL17A1 interaction and COL17A1 deubiquitination. Cycloheximide treatment was used to analyze COL17A1 protein stability.ResultsCOL17A1 and USP22 were upregulated in human LUAD tissues and cell lines. Functionally, COL17A1 knockdown acted for the suppression of LUAD cell growth, invasion, and migration as well as promotion of cell apoptosis and ferroptosis in vitro. COL17A1 knockdown could diminish the tumorigenicity of LUAD cells in vivo. Mechanistically, USP22 stabilized and upregulated COL17A1 by enhancing the deubiquitination of COL17A1. Additionally, reexpression of COL17A1 could reverse USP22 silencing‐induced phenotype changes of LUAD cells in vitro.ConclusionOur findings demonstrate that USP22‐stabilized COL17A1 possesses oncogenic activity in LUAD. We propose that USP22 and COL17A1 would be potential targets for the establishment of therapeutic approaches against LUAD.

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Metastasis and basement membrane-related signature enhances hepatocellular carcinoma prognosis and diagnosis by integrating single-cell RNA sequencing analysis and immune microenvironment assessment

Wei,

Tan,

Huang

et al. 2024

J Transl Med

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Background Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and second leading cause of cancer-related deaths worldwide. The heightened mortality associated with HCC is largely attributed to its propensity for metastasis, which cannot be achieved without remodeling or loss of the basement membrane (BM). Despite advancements in targeted therapies and immunotherapies, resistance and limited efficacy in late-stage HCC underscore the urgent need for better therapeutic options and early diagnostic biomarkers. Our study aimed to address these gaps by investigating and evaluating potential biomarkers to improve survival outcomes and treatment efficacy in patients with HCC. Method In this study, we collected the transcriptome sequencing, clinical, and mutation data of 424 patients with HCC from The Cancer Genome Atlas (TCGA) and 240 from the International Cancer Genome Consortium (ICGC) databases. We then constructed and validated a prognostic model based on metastasis and basement membrane-related genes (MBRGs) using univariate and multivariate Cox regression analyses. Five immune-related algorithms (CIBERSORT, QUANTISEQ, MCP counter, ssGSEA, and TIMER) were then utilized to examine the immune landscape and activity across high- and low-risk groups. We also analyzed Tumor Mutation Burden (TMB) values, Tumor Immune Dysfunction and Exclusion (TIDE) scores, mutation frequency, and immune checkpoint gene expression to evaluate immune treatment sensitivity. We analyzed integrin subunit alpha 3 (ITGA3) expression in HCC by performing single-cell RNA sequencing (scRNA-seq) analysis using the TISCH 2.0 database. Lastly, wound healing and transwell assays were conducted to elucidate the role of ITGA3 in tumor metastasis. Results Patients with HCC were categorized into high- and low-risk groups based on the median values, with higher risk scores indicating worse overall survival. Five immune-related algorithms revealed that the abundance of immune cells, particularly T cells, was greater in the high-risk group than in the low-risk group. The high-risk group also exhibited a higher TMB value, mutation frequency, and immune checkpoint gene expression and a lower tumor TIDE score, suggesting the potential for better immunotherapy outcomes. Additionally, scRNA-seq analysis revealed higher ITGA3 expression in tumor cells compared with normal hepatocytes. Wound healing scratch and transwell cell migration assays revealed that overexpression of the MBRG ITGA3 enhanced migration of HCC HepG2 cells. Conclusion This study established a direct molecular correlation between metastasis and BM, encompassing clinical features, tumor microenvironment, and immune response, thereby offering valuable insights for predicting clinical outcomes and immunotherapy responses in HCC.

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Identification of immune biomarkers associated with basement membranes in idiopathic pulmonary fibrosis and their pan-cancer analysis

Cited by 3 publications

References 98 publications

Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis

Genetic burden of dysregulated cytoskeletal organisation in the pathogenesis of pulmonary fibrosis

The Deubiquitinase USP22‐Stabilized COL17A1 Promotes Lung Adenocarcinoma Progression

Metastasis and basement membrane-related signature enhances hepatocellular carcinoma prognosis and diagnosis by integrating single-cell RNA sequencing analysis and immune microenvironment assessment

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