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Potentially Dysregulated Cholesterol, Cellular Interaction, Immune, and Extracellular Matrix in NTCU-Induced Lung Squamous Cell Carcinoma (LUSC) in Mice Model and LUSC Patients

ABSTRACT: Lung squamous cell carcinoma (LUSC) is associated with poor survival owing to the lack of advanced targeted therapies, due to the incomplete characterization of complex genetic profiles. Therefore, it is essential to elucidate the molecular mechanisms of LUSC via the mice model and human database to understand the LUSC pathogenesis. A LUSC BALB/c mice model was established using N-nitroso-tris-chloroethylurea (NTCU). After termination of mice, the lung tissues were subjected to RNA sequencing. First, DESeq2 was used to normalize the read count, followed by gene set enrichment analysis (GSEA) to identify the affected pathways in LUSC. Subsequently, the pathogenic single nucleotide polymorphism (SNP) was determined using Protein Variation Effect Analyzer (PROVEAN) and Sorting Intolerant From Tolerant (SIFT), following scores of < 0.05 and < -2.5, respectively, which were then functionally enriched using g:Profiler. The transcriptomic profile of human LUSC patients was obtained from The International Cancer Genome Consortium (ICGC) and analyzed. The impact of pathogenic simple somatic mutation in human LUSC was determined using the Combined Annotation Dependent Depletion (CADD) score, which was functionally enriched using g:Profiler. Additionally, the enriched pathway of LUSC patients with complete remission (responsive) was compared with those with disease progression or deceased (non-responsive) post-GSEA treatment. All pathway analysis was possibly referred to the Reactome database, and an adjusted p-value < 0.05 was considered statistically significant. Based on the transcriptomic analysis of LUSC mice, the top pathway enriched from the animal study and human LUSC revealed similarity in four major themes: cholesterol, cellular interaction, immune, and extracellular matrix dysregulation. Furthermore, the overrepresented pathways identified in LUSC patients were consistent with the four major themes dysregulated in LUSC tumors. This study identified several biological pathways that may contribute to LUSC development and potential targets for future LUSC therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE240837 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Squamous cell lung cancer (LUSC) is a frequently diagnosed histological subtype of lung malignancy associated with high mortality due to limited number of treatment options. Identification of potential targets suitable for drug development using high-throughput methods is still lacking. Therefore, the purpose of this research is to analyze expression profiles of mRNA and miRNA in LUSC, aiming to identify the key molecules associated with tumorigenesis and prognosis (overall survival; OS). We performed differential gene expression analysis, pathway enrichment analysis and gene ontology analysis on RNA-seq data obtained from 23 FFPE tumor samples and 3 FFPE healthy individuals. TCGA LUSC and GTEx healthy donors’ cohorts were used for validation. We identified 1133 up-regulated and 644 down-regulated genes, common for both cohorts. The most significant up-regulated genes were involved in cell-cycle regulation pathways, while down-regulated genes predominately belonged to immune-related pathways. Survival analysis performed on selected genes, commonly dysregulated in both cohorts and performed only on non-metastatic patients, identified novel prognostic biomarkers associated with OS in early-stage LUSC patients (HOXC4-worse OS, p=0.0001; LILRA5-better OS, p=0.0086). In total, 50 differentially expressed genes are correlated with patients’ OS. Aiming to get better insight into the profile of the tumor microenvironment, we estimated levels of immune-cells infiltration in LUSC and identified 4 subtypes based on immune-cell infiltration levels. Protein-protein interaction (PPI) network was built based on differentially expressed genes, and PPI modules and hub-genes were identified. Weighted gene co-expression network analysis was conducted to identify significant modules and hub-genes in correlation to clinical traits. Differential analysis on miRNA-Seq data, obtained from 16 tumor and 4 healthy tissue samples, was conducted as well. 75 up-regulated and 47 down-regulated miRNAs were identified. Further, targets of differentially expressed miRNA were identified, following gene ontology analysis and miRNA-mRNA networks construction.

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Potentially Dysregulated Cholesterol, Cellular Interaction, Immune, and Extracellular Matrix in NTCU-Induced Lung Squamous Cell Carcinoma (LUSC) in Mice Model and LUSC Patients

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