Elevated TUBA1A Might Indicate the Clinical Outcomes of Patients with Gastric Cancer, Being Associated with the Infiltration of Macrophages in the Tumor Immune Microenvironment

Background and Aims: TUBA1A belongs to the tubulin superfamily, and its role in gastric cancer (GC) remains unclear. This study assessed the expression and effect of TUBA1A in GC, as well as its association with survival and clinicopathological features. Gene set enrichment analysis (GSEA) results revealed that high TUBA1A expression was associated with multiple pathways, including those that contributed to the infiltration of macrophages in the tumor microenvironment. Since increased infiltration of macrophages can lead to oxaliplatin resistance, we analyzed the association between TUBA1A, the infiltration of macrophages to the tumor microenvironment, and the inhibitory concentration 50% (IC50) of oxaliplatin. In addition, we analyzed the possible epigenetic regulation mechanism. Methods: A total of 1,881 samples, including 1,618 patients with GC and 263 normal samples, were examined. The associations between clinicopathological features and TUBA1A were assessed by chi-square test, survival was assessed by Kaplan-Meier analysis, and gene set enrichment analysis (GSEA) was performed to explore the potential mechanisms. The associations between TUBA1A and immune infiltration of M0-, M1-, and M2- polarized macrophages were examined by applying deconvolution’s quantification and Pearson’s correlation analysis. The association of TUBA1A with the IC50 of oxaliplatin was analyzed by Pearson correlation test. The mechanisms of TUBA1A dysregulation were studied by analyzing methylation data. A single-cell TUBA1A mRNA expression map of the stomach was drawn from the analysis of stomach single-cell RNA sequencing data that included more than 13,000 single cells of 17 stomach cell types. Results: TUBA1A expression was elevated in GC (p<0.01) and indicated poorer overall survival (p<0.001), first progression survival (p<0.001), and post-progression survival (p<0.01). High TUBA1A expression was significantly correlated with more aggressive clinicopathological features of GC patients (p<0.001). Elevated TUBA1A contributes to the infiltration of macrophages to the tumor microenvironment (p<0.001) and increased the IC50 of oxaliplatin in vitro (p<0.05), while hypomethylation was shown to contribute to the upregulation of TUBA1A (p<0.05). Conclusions: TUBA1A might be a potential prognostic marker and therapeutic target in GC. TUBA1A is significantly associated with the infiltration of M2-polarized macrophages in GC, and the IC50 of oxaliplatin. Hypomethylation contributes to the upregulation of TUBA1A in GC.

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m6A-Mediated Tumor Invasion and Methylation Modification in Breast Cancer Microenvironment

Journal of Oncology ◽

10.1155/2021/9987376 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Fei Liu ◽

Xiaopeng Yu ◽

Guijin He

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Immune Cell ◽

Principal Component ◽

Enrichment Analysis ◽

Genomic Variation ◽

Gene Set Enrichment Analysis ◽

Single Sample ◽

Gene Set Enrichment ◽

Gene Set

Background. We analyzed the n6-methyladenosine (m6A) modification patterns of immune cells infiltrating the tumor microenvironment of breast cancer (BC) to provide a new perspective for the early diagnosis and treatment of BC. Methods. Based on 23 m6A regulatory factors, we identified m6A-related gene characteristics and m6A modification patterns in BC through unsupervised cluster analysis. To examine the differences in biological processes among various m6A modification modes, we performed genomic variation analysis. We then quantified the relative infiltration levels of different immune cell subpopulations in the tumor microenvironment of BC using the CIBERSORT algorithm and single-sample gene set enrichment analysis. Univariate Cox analysis was used to screen for m6A characteristic genes related to prognosis. Finally, we evaluated the m6A modification pattern of patients with a single BC by constructing the m6Ascore based on principal component analysis. Results. We identified three different m6A modification patterns in 2128 BC samples. A higher abundance of the immune infiltration of the m6Acluster C was indicated by the results of CIBERSORT and the single-sample gene set enrichment analysis. Based on the m6A characteristic genes obtained through screening, the m6Ascore was determined. The BC patients were segregated into m6Ascore groups of low and high categories, which revealed significant survival benefits among patients with low m6Ascores. Additionally, the high-m6Ascore group had a higher mutation frequency and was associated with low PD-L1 expression, and the m6Ascore and tumor mutation burden showed a positive correlation. In addition, treatment effects were better in patients in the high-m6Ascore group. Conclusions. In case of a single patient with BC, the immune cell infiltration characteristics of the tumor microenvironment and the m6A methylation modification pattern could be evaluated using the m6Ascore. Our results provide a foundation for improving personalized immunotherapy of BC.

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Identification of Pro-Fibrotic Macrophage Populations by Single-Cell Transcriptomic Analysis in West Highland White Terriers Affected With Canine Idiopathic Pulmonary Fibrosis

Frontiers in Immunology ◽

10.3389/fimmu.2020.611749 ◽

2020 ◽

Vol 11 ◽

Author(s):

Aline Fastrès ◽

Dimitri Pirottin ◽

Laurence Fievez ◽

Alexandru-Cosmin Tutunaru ◽

Géraldine Bolen ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Single Cell ◽

Enrichment Analysis ◽

Lavage Fluid ◽

Gene Set Enrichment Analysis ◽

Cell Populations ◽

Gene Set Enrichment ◽

Gene Set ◽

Macrophage Populations

Canine idiopathic pulmonary fibrosis (CIPF) affects old dogs from the West Highland white terrier (WHWT) breed and mimics idiopathic pulmonary fibrosis (IPF) in human. The disease results from deposition of fibrotic tissue in the lung parenchyma causing respiratory failure. Recent studies in IPF using single-cell RNA sequencing (scRNA-seq) revealed the presence of profibrotic macrophage populations in the lung, which could be targeted for therapeutic purpose. In dogs, scRNA-seq was recently validated for the detection of cell populations in bronchoalveolar lavage fluid (BALF) from healthy dogs. Here we used the scRNA-seq to characterize disease-related heterogeneity within cell populations of macrophages/monocytes (Ma/Mo) in the BALF from five WHWTs affected with CIPF in comparison with three healthy WHWTs. Gene set enrichment analysis was also used to assess pro-fibrotic capacities of Ma/Mo populations. Five clusters of Ma/Mo were identified. Gene set enrichment analyses revealed the presence of pro-fibrotic monocytes in higher proportion in CIPF WHWTs than in healthy WHWTs. In addition, monocyte-derived macrophages enriched in pro-fibrotic genes in CIPF compared with healthy WHWTs were also identified. These results suggest the implication of Ma/Mo clusters in CIPF processes, although, further research is needed to understand their role in disease pathogenesis. Overexpressed molecules associated with pulmonary fibrosis processes were also identified that could be used as biomarkers and/or therapeutic targets in the future.

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Mining the TCGA Database for Microenvironment‐Related Genes with Prognostic Value in Gastric Cancer

10.21203/rs.3.rs-175261/v1 ◽

2021 ◽

Author(s):

Ting Liu ◽

Zheng Gong ◽

Hong Zhang ◽

Yi Wan ◽

Ming-Han Ren ◽

...

Keyword(s):

Gastric Cancer ◽

Distant Metastasis ◽

Clinical Stage ◽

Enrichment Analysis ◽

Clinicopathological Characteristics ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Gene Set Enrichment ◽

Gene Set ◽

Protein Protein Interaction

Abstract BackgroundGastric cancer (GC) is the fifth most common cancer worldwide. Previous studies have suggested that the tumor microenvironment (TME) plays an important role in the development and prognosis of GC. In this study, we aimed to identify genes in tumor-infiltrating immune cells (TICs) that influence the progression and prognosis of GC. MethodsWe used the ESTIMATE algorithm to calculate the scores of the stromal and immune components of the TME in 407 GC samples collected from The Cancer Genome Atlas (TCGA) database.The differentially expressed genes (DEGs) were intersected by a protein-protein interaction (PPI) network and analyzed by univariate Cox regression.Further analysis showed the correlation between MCEMP1 and the clinicopathological characteristics of GC patients (clinical stage, distant metastasis) and survival.Then we used Gene set enrichment analysis (GSEA) and CIBERSORT analysis to examine the relationship between MCEMP1 and the TME.ResultsThe analysis revealed that the expression of MCEMP1 was positively correlated with the clinicopathological characteristics of GC patients (clinical stage, distant metastasis) and negatively correlated with survival. Gene set enrichment analysis (GSEA) indicated that gene sets in the MCEMP1 high expression group were concentrated mainly in immune-related pathways. CIBERSORT analysis of the proportion of TICs revealed that neutrophils and M2 macrophages were positively correlated with MCEMP1 expression, suggesting that MCEMP1 is responsible for preservation of the immune-dominant status of the TME. ConclusionHigh MCEMP1 expression might be a biomarker of a poor prognosis in GC patients and provide a clue regarding the different statuses of the TME, offering additional insight into therapy for GC.

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Abstract 4411: A gene set enrichment analysis approach in single-cells along pseudotime trajectories reveals the dynamic activity of oncogenic pathways

10.1158/1538-7445.am2020-4411 ◽

2020 ◽

Author(s):

Alexander T. Wenzel ◽

Devora Champa ◽

Stephen B. Howell ◽

Jill P. Mesirov ◽

Olivier Harismendy

Keyword(s):

Single Cells ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Analysis Approach ◽

Gene Set Enrichment ◽

Dynamic Activity ◽

Gene Set ◽

Oncogenic Pathways

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HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.603480 ◽

2020 ◽

Vol 10 ◽

Author(s):

Ce Ji ◽

Li-Sha Sun ◽

Fei Xing ◽

Nan Niu ◽

Hong-Li Gao ◽

...

Keyword(s):

Gastric Cancer ◽

Multivariate Analysis ◽

Confidence Interval ◽

Enrichment Analysis ◽

Hazard Ratio ◽

Gene Set Enrichment Analysis ◽

Signal Pathways ◽

Gene Set Enrichment ◽

Gene Set ◽

The Impact

HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.

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ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer

Scientific Reports ◽

10.1038/s41598-021-90330-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yangming Hou ◽

Yingjuan Xu ◽

Dequan Wu

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Tumor Promoter ◽

Protein Protein Interaction ◽

Oxidative Phosphorylation Pathway ◽

Cox Proportional Hazard Regression

AbstractThe infiltration degree of immune and stromal cells has been shown clinically significant in tumor microenvironment (TME). However, the utility of stromal and immune components in Gastric cancer (GC) has not been investigated in detail. In the present study, ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cell (TIC) in GC cohort, including 415 cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were screened by Cox proportional hazard regression analysis and protein–protein interaction (PPI) network construction. Then ADAMTS12 was regarded as one of the most predictive factors. Further analysis showed that ADAMTS12 expression was significantly higher in tumor samples and correlated with poor prognosis. Gene Set Enrichment Analysis (GSEA) indicated that in high ADAMTS12 expression group gene sets were mainly enriched in cancer and immune-related activities. In the low ADAMTS12 expression group, the genes were enriched in the oxidative phosphorylation pathway. CIBERSORT analysis for the proportion of TICs revealed that ADAMTS12 expression was positively correlated with Macrophages M0/M1/M2 and negatively correlated with T cells follicular helper. Therefore, ADAMTS12 might be a tumor promoter and responsible for TME status and tumor energy metabolic conversion.

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Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis

Journal of Clinical Medicine ◽

10.3390/jcm8101580 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1580 ◽

Cited By ~ 1

Author(s):

Kyoung Min Moon ◽

Kyueng-Whan Min ◽

Mi-Hye Kim ◽

Dong-Hoon Kim ◽

Byoung Kwan Son ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Respiratory Failure ◽

Scrub Typhus ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Acid Base ◽

Gene Set Enrichment ◽

Gene Set ◽

Gene Sets

Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.

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Drug perturbation gene set enrichment analysis (dpGSEA): a new transcriptomic drug screening approach

BMC Bioinformatics ◽

10.1186/s12859-020-03929-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Mike Fang ◽

Brian Richardson ◽

Cheryl M. Cameron ◽

Jean-Eudes Dazard ◽

Mark J. Cameron

Keyword(s):

Drug Targets ◽

T Regulatory Cells ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Regulatory Cells ◽

Gene Set Enrichment ◽

Gene Set ◽

Gene Sets ◽

Gastroenteropancreatic Neuroendocrine Tumor ◽

Public Datasets

Abstract Background In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets. Results We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting. Conclusions dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.

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