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A prognostic gene signature for gastric cancer and the immune infiltration-associated mechanism underlying the signature gene, PLG

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Abstract

Background

Globally, gastric cancer (GC) is a common and lethal solid malignant tumor. Identifying the molecular signature and its functions can provide mechanistic insights into GC development and new methods for targeted therapy.

Methods

Differentially expressed genes (DEGs) and prognostic genes (from univariate Cox regression analysis) were overlapped to obtain prognostic DEGs. Subsequently, molecular modules and the functions of these prognostic DEGs were identified by Metascape and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)/Gene Set Enrichment Analysis (GSEA) enrichment analyses, respectively. Protein–protein interaction (PPI) networks of up- and down-regulated prognostic DEGs in GC were analyzed using the MCC algorithm of the Cytohubba plug-in in Cytoscape. The prognostic gene signature was defined on hub genes of the PPI networks by least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. Furthermore, the expressional level of PLG in our clinical GC samples was validated by quantitative PCR (qPCR), western blotting, and immunohistochemistry (IHC). Subsequently, the PLG expression-correlation analysis was performed to assess the role of PLG in GC progression. Immune infiltration analysis was performed by single-sample gene set enrichment analysis (ssGSEA) to assess the inhibitory effect of PLG on immune infiltration.

Results

Firstly, Up- and down-regulated prognostic DEGs and hub genes in protein–protein interaction (PPI) networks in GC were identified. A prognostic five-gene signature (i.e., PLG, SPARC, FGB, SERPINE1, and KLHL41) was identified. Among the five genes, the relationship between plasminogen (PLG) and GC remains largely unclear. Moreover, the functions of PLG-correlated genes in GC, like 'fibrinolysis', 'hemostasis', 'ion channel complex', and 'transporter complex' were identified. In addition, PLG expression correlated negatively with the infiltration of almost all immune cell types. Interestingly, the expression of PLG was significantly and highly correlated with that of CD160, an immune checkpoint inhibitor.

Conclusion

Our findings defined a new five-gene signature for predicting GC prognosis, but more validation is required to assess the effects and mechanism of the five genes, especially PLG, for the development of new GC therapies.

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Availability of data and materials

Publicly available datasets were analyzed in this study. The data can be found here: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi (GEO datasets), https://xenabrowser.net/datapages/ (TCGA datasets).

Abbreviations

aDC:

Activated dendritic cells

cDC:

Conventional dendritic cells

iDC:

Immature dendritic cells

pDC:

Plasmacytoid dendritic cells

Tcm:

Central memory T-cells

Tem:

Effector memory T cells

Tgd:

T cells gamma delta

TFH:

T follicular helper cells

CESC:

Cervical squamous cell carcinoma and endocervical adenocarcinoma

CHOL:

Cholangiocarcinoma

COAD:

Colon adenocarcinoma

GBM:

Glioblastoma multiforme

STAD:

Stomach adenocarcinoma

KICH:

Kidney chromophobe renal cell carcinoma

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

LAML:

Acute myeloid leukemia

LGG:

Brain lower grade glioma

LIHC:

Liver hepatocellular carcinoma

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

PAAD:

Pancreatic adenocarcinoma

STAD:

Stomach adenocarcinoma

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Funding

Youth Culture Program of First Affiliated Hospital, Anhui Medical University (2020kj04 to SZ), Research Funding for Doctoral Talents of First Affiliated Hospital, Anhui Medical University (1513 to SZ), and Scientific Research of BSKY from Anhui Medical University (XJ201935 to ML).

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Author notes

  1. Hui Shi, Jiangling Duan, and Zhangming Chen have contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, No.81, Mei Shan Road, Hefei, 230032, Anhui, China

    Hui Shi, Jiangling Duan, Rui Kong, Xiuyin Guan, Zhen Qi & Ming Lu

  2. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Zhangming Chen & Wenxiu Han

  3. Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Mengqi Huang

  4. Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, No.218, Ji Xi Road, Hefei, 230032, Anhui, China

    Shuang Zheng

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Contributions

HS, JD, ZC and ML: searched data, analyzed data, and wrote the manuscript. RK, XG, SQ: analyzed data. HS, JD, ZC, MH and WH: collect clinical samples and did experiments. SZ and ML: edited the manuscript. SZ and ML: conception of the project.

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Correspondence to Shuang Zheng or Ming Lu.

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Shi, H., Duan, J., Chen, Z. et al. A prognostic gene signature for gastric cancer and the immune infiltration-associated mechanism underlying the signature gene, PLG. Clin Transl Oncol 25, 995–1010 (2023). https://doi.org/10.1007/s12094-022-03003-6

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