Genetic pathway analysis reveals a major role for extracellular matrix organization in inflammatory and neuropathic pain

Abstract Background: Prognostic prediction models have been developed to detect new biomarkers of gastric cancer (GC). The identification of new biomarkers could provide theoretical foundations for the application of molecular targeted therapy in advanced GC. The aim of this study was to construct a prognostic prediction model for stomach adenocarcinoma (STAD) based on The Cancer Genome Atlas (TCGA) database. Methods: First, we used the "limma" package to screen differentially expressed genes (DEGs) based on TCGA database. Gene ontology (GO) analysis was performed using the "ClusterProfiler" package. The interactions between proteins and the relationships between differentially expressed genes and clinical features were analyzed by protein-protein interaction (PPI) network analysis and weighted gene coexpression network analysis (WGCNA), respectively. Then, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to identify differentially enriched pathways. The GenVisR package and CIBERSORT were used to identify mutations and assess immune infiltration. Finally, the expression of COL3A1 in STAD tissues was verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting.Results: Six differentially expressed genes were screened out, namely, COL3A1, ADAMTS12, BGN, FNDC1, AEBP1 and HTRA3. The enrichment results showed that differentially expressed genes were involved in multiple pathways in STAD, such as those related to the extracellular matrix, extracellular structure organization, and extracellular matrix organization. The differentially expressed genes were related to immune infiltration via the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways. The western blotting and RT-qPCR results suggested that COL3A1 was overexpressed in STAD tissues compared with normal tissues.Conclusion: COL3A1, ADAMTS12, BGN, FNDC1, AEBP1 and HTRA3 could play important roles in the tumorigenesis and progression of STAD via various pathways, including those involving the extracellular matrix, extracellular structure organization, and extracellular matrix organization. COL3A1, ADAMTS12, BGN, FNDC1, AEBP1, and HTRA3 act as oncogenes in most cancers and may be biomarkers. Additionally, the identification of COL3A1 as a candidate biomarker provides a direction for further research on the role of tumor immunity in gastric cancer.

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Statistical inference of genetic pathway analysis in high dimensions

Biometrika ◽

10.1093/biomet/asz033 ◽

2019 ◽

Vol 106 (3) ◽

pp. 651-651

Author(s):

Yang Liu ◽

Wei Sun ◽

Alexander P Reiner ◽

Charles Kooperberg ◽

Qianchuan He

Keyword(s):

Statistical Inference ◽

Pathway Analysis ◽

Genetic Variants ◽

Error Control ◽

Genome Wide Association Study ◽

Type I Error ◽

High Density Lipoproteins ◽

Type I ◽

Genetic Pathway ◽

A Genome

Summary Genetic pathway analysis has become an important tool for investigating the association between a group of genetic variants and traits. With dense genotyping and extensive imputation, the number of genetic variants in biological pathways has increased considerably and sometimes exceeds the sample size $n$. Conducting genetic pathway analysis and statistical inference in such settings is challenging. We introduce an approach that can handle pathways whose dimension $p$ could be greater than $n$. Our method can be used to detect pathways that have nonsparse weak signals, as well as pathways that have sparse but stronger signals. We establish the asymptotic distribution for the proposed statistic and conduct theoretical analysis on its power. Simulation studies show that our test has correct Type I error control and is more powerful than existing approaches. An application to a genome-wide association study of high-density lipoproteins demonstrates the proposed approach.

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Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF‐β signaling as primary targets

The FASEB Journal ◽

10.1096/fj.15-279869 ◽

2016 ◽

Vol 30 (5) ◽

pp. 1741-1756 ◽

Cited By ~ 34

Author(s):

Mourad Bekhouche ◽

Cedric Leduc ◽

Laura Dupont ◽

Lauriane Janssen ◽

Frederic Delolme ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Organization

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The use of glutathione to reduce oxidative stress status and its potential for modifying the extracellular matrix organization in cleft lip

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.455 ◽

2021 ◽

Author(s):

Rong LI ◽

Chen HUANG ◽

Jeff Cheuk Hin HO ◽

Cherry Chi Tim LEUNG ◽

Richard Yuen Chong KONG ◽

...

Keyword(s):

Oxidative Stress ◽

Extracellular Matrix ◽

Cleft Lip ◽

Oxidative Stress Status ◽

Matrix Organization

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OP0233 Genome-Wide Pathway Analysis Reveals that VEGF Genetic Pathway Is Associated with Oral Ulcers in Systemic Lupus Erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-eular.3571 ◽

2016 ◽

Vol 75 (Suppl 2) ◽

pp. 146.1-146

Author(s):

A. Julià ◽

P. Carreira ◽

R. Blanco ◽

V. Martínez Taboada ◽

L. Carreño Pérez ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Pathway Analysis ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Genetic Pathway ◽

Oral Ulcers ◽

Genome Wide

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Regulation of Extracellular Matrix Organization by BMP Signaling in Caenorhabditis elegans

PLoS ONE ◽

10.1371/journal.pone.0101929 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101929 ◽

Cited By ~ 16

Author(s):

Robbie D. Schultz ◽

Emily E. Bennett ◽

E. Ann Ellis ◽

Tina L. Gumienny

Keyword(s):

Extracellular Matrix ◽

Caenorhabditis Elegans ◽

Bmp Signaling ◽

Matrix Organization

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Undersulfation of proteoglycans and proteins alter C6 glioma cells proliferation, adhesion and extracellular matrix organization

International Journal of Developmental Neuroscience ◽

10.1016/s0736-5748(02)00081-3 ◽

2002 ◽

Vol 20 (7) ◽

pp. 563-571 ◽

Cited By ~ 12

Author(s):

Claudia B.N. Mendes de Aguiar ◽

Ricardo Castilho Garcez ◽

Marcio Alvarez‐Silva ◽

Andréa Gonçalves Trentin

Keyword(s):

Extracellular Matrix ◽

Glioma Cells ◽

C6 Glioma ◽

C6 Glioma Cells ◽

Matrix Organization

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Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot

PLoS ONE ◽

10.1371/journal.pone.0241476 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0241476

Author(s):

Chad S. Weldy ◽

Saad Ali Syed ◽

Myriam Amsallem ◽

Dong-Qing Hu ◽

Xuhuai Ji ◽

...

Keyword(s):

Cell Cycle ◽

Extracellular Matrix ◽

Fatty Acid ◽

Tetralogy Of Fallot ◽

Hierarchical Clustering ◽

Pathway Analysis ◽

Mirna Expression ◽

Peripheral Blood ◽

Systolic Function ◽

Whole Genome

Introduction The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure. Methods Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent’s global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection. Results MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1α signaling was downregulated while p53 signaling was predicted to be upregulated. Conclusion Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.

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