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Identification of Key Genes and Signaling Pathways Associated with the Progression of Gastric Cancer

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Genomic features have been gradually regarded as part of the fundamentals to the clinical diagnosis and treatment for gastric cancer. However, the molecular alterations taking place during the progression of gastric cancer remain unclear. Therefore, identification of potential key genes and pathways in the gastric cancer progression is crucial to clinical practices. The gene expression profile, GSE103236, was retrieved for the identification of the differentially expressed genes (DEGs), followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichments, gene set enrichment analysis (GSEA) and the protein-protein interaction (PPI) networks. Multiple bioinformatics platforms were employed for expression and prognostic analysis. Fresh frozen gastric cancer tissues were used for external validation. A total of 161 DEGs were identified from GSE103236. The PPI network-derived hub genes included collagen type I alpha 1 chain (COL1A1), tissue inhibitor of the metalloproteinases (TIMP1), Secreted Phosphoprotein 1 (SPP1), somatostatin (SST), neuropeptide Y (NPY), biglycan (BGN), matrix metallopeptidase 3 (MMP3), apolipoprotein E (APOE), ATPase H+/K+ transporting alpha subunit (ATP4A), lysyl oxidase (LOX). SPP1 (log rank p = 0.0048, HR = 1.39 [1.1–1.75]) and MMP3 (log rank p < 0.0001, HR = 1.77 [1.44–2.19]) were significantly associated with poor overall survival. Stage-specifically, both COL1A1 and BGN were correlated with significant in stage III and IV gastric cancer cases. LOX showed significant correlation with prognosis in stage I and stage II gastric cancer cases. Furthermore, cg00583003 of SPP1 and cg16466334 of MMP3 exhibited highly methylation level and significant prognostic values (SPP1: HR = 1.625, p = 0.013; MMP3: HR = 0.647, p = 0.011). Hub genes signature displayed a favorable prognostic value (p value = 5.227e-05). APOE demonstrated the highest correlation with CD8+ T cells, neutrophils, and dendritic cells whereas BGN had the highest correlation with macrophages. This study systematically explored the key genes and pathways involved in PGC and AGC, providing insights into therapeutic individualized management.

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Data Availability

The datasets supporting the conclusion of this article were included within the article.

Abbreviations

GC:

Gastric cancer

DEGs:

Differentially expressed genes

PGC:

Primary gastric cancer

AJCC:

American Joint Committee on Cancer

AGC:

Advanced gastric cancer

GEO:

Gene Expression Omnibus

TCGA:

The Cancer Genome Atlas

GSEA:

Gene set enrichment analysis

PPI:

Protein-protein interaction

FC:

Fold changes

GO:

Gene ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

DAVID:

Database for Annotation, Visualization and Integrated Discovery

FDR:

False discovery rate

STRING:

Search Tool for the Retrieval of Interacting Genes

MCODE:

Molecular Complex Detection

GEPIA:

Gene Expression Profiling Interactive Analysis

GTEx:

Genotype-tissue expression

STAD:

Stomach adenocarcinoma

HPA:

Human protein atlas

qRT-PCR:

Quantitative real-time PCR

KM:

Kaplan-Meier

OS:

Overall survival

HR:

Hazard ratio

95% CI:

95% confidence intervals

TIMER:

Tumor IMmune Estimation Resource

BP:

Biological process

CC:

Cellular component

MF:

Molecular function

COL1A1:

Collagen type I alpha 1 chain

TIMP1:

Tissue inhibitor of the metalloproteinases

SPP1:

Secreted Phosphoprotein 1

SST:

Somatostatin

NPY:

Neuropeptide Y

BGN:

Biglycan

MMP3:

Matrix metallopeptidase 3

APOE:

Apolipoprotein E

ATP4A:

ATPase H+/K+ transporting alpha subunit

LOX:

Lysyl oxidase

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Acknowledgements

We would like to thank Dr. Meng-Kai Ge (Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine) for experimental assistance. We would like to thank the academic supports from the biobank of Shanghai Minimally Invasive Surgery Center at Ruijin Hospital. We would like to thank Jiexuan Wang (Ruijin Hospital, Shanghai Jiao Tong University School of Medicine) for his contribution in samples preparation.

Funding

The study is financially supported by National Natural Science Foundation of China (NSFC) (81402423, 81572818, 81871984), Shanghai Municipal Commission of Health and Family Planning (2017YQ062), as well as Shanghai Science and Technology Committee (18695841400).

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Chaoran Yu, Jie Chen, Junjun Ma, Lu Zang, Feng Dong, Jing Sun & Minhua Zheng

  2. Department of Nursing, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China

    Jie Chen

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  1. Chaoran Yu
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Contributions

CY, JC and JM carried out experiments and data analysis;

CY, JS, JC, LZ, and MZ drafted the manuscript;

CY, JS, LZ, and MZ participated in study design and data collection;

All authors read and approved the final manuscript.

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Correspondence to Chaoran Yu.

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All authors declare no conflict of interest in this study.

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All the subjects have given their written informed consent. The study protocol has been approved by the research institute’s committee on human research. No animal experiment is applicable.

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Chaoran Yu, Jie Chen and Junjun Ma contributed as co-first authors.

Minhua Zheng and Jing Sun are listed as corresponding authors (equally contributed).

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Yu, C., Chen, J., Ma, J. et al. Identification of Key Genes and Signaling Pathways Associated with the Progression of Gastric Cancer. Pathol. Oncol. Res. 26, 1903–1919 (2020). https://doi.org/10.1007/s12253-019-00781-3

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