Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul 16:12:724741.
doi: 10.3389/fimmu.2021.724741. eCollection 2021.

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

Xu-Sheng Liu  1   2 , Lu-Meng Zhou  3 , Ling-Ling Yuan  4 , Yan Gao  1 , Xue-Yan Kui  1 , Xiao-Yu Liu  1 , Zhi-Jun Pei  1   2
Affiliations

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

Xu-Sheng Liu et al. Front Immunol. .

Erratum in

Abstract

Background: Overexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).

Methods: TCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.

Results: NPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (YTHDF2) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).

Conclusion: NPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

Keywords: NPM1; glycolysis; immune infiltration; lung adenocarcinoma; m6A modification.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The expression of NPM1 in lung adenocarcinoma (LUAD) and pan-carcinoma. (A) NPM1 mRNA expression levels in pan-cancer were measured using Oncomine. (B) Pan-cancer data downloaded from the TCGA data sets were used to assess NPM1 mRNA expression levels. (C) Difference in expression of NPM1 between LUAD and matched normal tissues in TCGA data sets. (D) Difference in expression of NPM1 between LUAD and normal tissues in GSE31210 data sets. (E) The survival curve of NPM1. (F) ROC curve analysis of NPM1 diagnosis. (G) Difference of expression of NPM1 in LUAD cell lines and human normal lung epithelial cell lines. (H) Immunohistochemistry assay was used to analyze the expression of NPM1 in LUAD tissues and paracarcinoma tissues. (I) The mean NPM1 IHC score in LUAD tissue was significantly higher than that of matched paracarcinoma tissue. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ns, not significant.
Figure 2
Figure 2
Relationship between NPM1 mRNA expression and clinicopathological parameters in lung adenocarcinoma (LUAD) patients. The NPM1 mRNA expression level was expressed by using ggplot2 package of R software for the patient characteristics of (A) age, (B) gender, (C) pathologic stage, (D) T stage, (E) N stage, (F) M stage, (G) OS event, (H) DSS event and (I) PFI event. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ns, not significant.
Figure 3
Figure 3
Enrichment analysis of NPM1 gene co-expression network in lung adenocarcinoma (LUAD). (A) Volcano map showed co-expression genes associated with NPM1 expression in TCGA LUAD data sets. (B, C) Heat maps showed the top 50 co-expression genes positively and negatively correlated with NPM1 expression in the LUAD data sets. (D–F) Enrichment analysis of gene ontology (GO) terms for NPM1 co-expression genes. (G) Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for terms for NPM1 co-expression genes.
Figure 4
Figure 4
Gene Set Enrichment Analysis. Pathway enriched in the p53 hypoxia pathway (A) mTORC1 mediated signaling (B) signaling by EGFR in cancer (C) antigen activates B cell receptor BCR leading to generation of second messengers (D) methylation (E) and aerobic glycolysis (F).
Figure 5
Figure 5
Correlation between NPM1 and Tumor Immune Infiltrating Cells. (A) Correlation between the expression of NPM1 and immune infiltrating cells in lung adenocarcinoma (LUAD). (B) NPM1 CNV affects the infiltrating levels of B cell, CD4+ T cell, macrophages, neutrophils and dendritic cell in LUAD. (C) Changes of 22 immune cell subtypes between high and low NPM1 expression groups in LUAD tumor samples. (D) Kaplan-Meier plots of immune infiltration and NPM1 expression levels in LUAD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ns, not significant.
Figure 6
Figure 6
NPM1 expression correlated with B cell and natural killer cell in lung adenocarcinoma (LUAD). Markers include CD19, MS4A1 and CD79A of B cell (A) B3GAT1, KIR3DL1 and CD7 of natural killer cell (B).
Figure 7
Figure 7
Correlations of NPM1 expression with m6A related genes in lung adenocarcinoma (LUAD). (A) GSE31210 and TCGA LUAD data sets analyzed the correlation between the NPM1 and the m6A related genes expression in LUAD. (B) Draw a scatter plot to show the correlation between the NPM1 and the m6A related genes expression, include ALKBH5, HNRNPC, IGF2BP1 and YTHDF2. (C) The differential expression of m6A related genes between high and low NPM1 expression groups in LUAD tumor samples. (D) Venn diagram showed both expression correlation and differential expression of genes, including HNRNPC and YTHDF2. (E) Kaplan-Meier curve of HNRNPC and YTHDF2. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ns, not significant.
Figure 8
Figure 8
Correlations of NPM1 expression with glycolysis related genes in lung adenocarcinoma (LUAD). (A) GSE31210 and TCGA LUAD data sets analyzed the correlation between the NPM1 and the m6A related genes expression in LUAD. (B) Draw a scatter plot to show the correlation between the NPM1 and the glycolysis related genes expression, include ENO1, G6PD, HK2, LDHA, LDHB, PDK3, PGK1 and SLC2A1. (C) The differential expression of glycolysis related genes between high and low NPM1 expression groups in LUAD tumor samples. (D) Venn diagram showed both expression correlation and differential expression of genes, including ENO1, HK2, LDHA, LDHB, PGK1 and SLC2A1. (E) Kaplan-Meier curve of ENO1, HK2, LDHA, LDHB, PGK1 and SLC2A1. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ns, not significant.
Figure 9
Figure 9
Correlations of NPM1 expression with glycolytic metabolism in lung adenocarcinoma (LUAD). (A) Representative PET/CT images and NPM1 immunohistochemical images of LUAD patients with FDG high uptake and FDG low uptake (SUVmax). (B) Statistical analysis of NPM1 expression in LUAD patients with FDG high uptake and patients with FDG low uptake. (C) Correlation between FDG uptake and NPM1 expression in 40 LUAD patients. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer J Clin (2021) 71(3):209–49. 10.3322/caac.21660 - DOI - PubMed
    1. Li Y, Sheng H, Ma F, Wu Q, Huang J, Chen Q, et al. RNA M6a Reader YTHDF2 Facilitates Lung Adenocarcinoma Cell Proliferation and Metastasis by Targeting the AXIN1/Wnt/β-Catenin Signaling. Cell Death Dis (2021) 12(5):479. 10.1038/s41419-021-03763-z - DOI - PMC - PubMed
    1. López DJ, Rodríguez JA, Bañuelos S. Nucleophosmin, a Multifunctional Nucleolar Organizer With a Role in DNA Repair. Biochim Biophys Acta (BBA) Proteins Proteomics (2020) 1868(12):140532. 10.1016/j.bbapap.2020.140532 - DOI - PubMed
    1. Karimi Dermani F, Gholamzadeh Khoei S, Afshar S, Amini R. The Potential Role of Nucleophosmin (NPM1) in the Development of Cancer. J Cell Physiol (2021). 10.1002/jcp.30406 - DOI - PubMed
    1. Zarka J, Short NJ, Kanagal-Shamanna R, Issa GC. Nucleophosmin 1 Mutations in Acute Myeloid Leukemia. Genes-Basel (2020) 11(6):649. 10.3390/genes11060649 - DOI - PMC - PubMed

Publication types