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. 2022 Jun 29:15:906762.
doi: 10.3389/fnmol.2022.906762. eCollection 2022.

Expression and Prognostic Role of Glia Maturation Factor-γ in Gliomas

Junhui Liu  1   2 , Xiaonan Zhu  1 , Lun Gao  1 , Rongxin Geng  1 , Xiang Tao  1 , Haitao Xu  1 , Zhibiao Chen  1
Affiliations

Expression and Prognostic Role of Glia Maturation Factor-γ in Gliomas

Junhui Liu et al. Front Mol Neurosci. .

Abstract

Background: Glia maturation factor-γ (GMFG) regulates actin cytoskeletal organization and promotes the invasion of cancer cells. However, its expression pattern and molecular function in gliomas have not been clearly defined.

Methods: In this study, public datasets comprising 2,518 gliomas samples were used to explore GMFG expression and its correlation with malignancy in gliomas. Immunohistochemistry (IHC) staining was performed to determine the expression of GMFG in gliomas using an in-house cohort that contained 120 gliomas samples. Gene ontology enrichment analysis was conducted using the DAVID tool. The correlation between GMFG expression and immune cell infiltration was evaluated using TIMER, Tumor Immune Single-Cell Hub (TISCH) database, and IHC staining assays. The Kaplan-Meier analysis was performed to determine the prognostic role of GMFG and its association with temozolomide (TMZ) response in gliomas.

Results: The GMFG expression was higher in gliomas compared with non-tumor brain tissues both in public datasets and in-house cohort. High expression of GMFG was significantly associated with WHO grade IV, IDH 1/2 wild-type, and mesenchymal (ME) subtypes. Bioinformatic prediction and IHC analysis revealed that GMFG expression obviously correlated with the macrophage marker CD163 in gliomas. Moreover, both lower grade glioma (LGG) and glioblastoma multiforme (GBM) patients with high GMFG expression had shorter overall survival than those with low GMFG expression. These results indicate that GMFG may be a therapeutic target for the treatment of such patients. Patients with low GMFG expression who received chemotherapy had a longer survival time than those with high GMFG expression. For patients who received ion radiotherapy (IR) only, the GMFG expression level had no effect on the overall survival neither in CGGA and TCGA datasets.

Conclusion: The GMFG is a novel prognostic biomarker for patients with both LGG and GBM. Increased GMFG expression is associated with tumor-associated macrophages (TAMs) infiltration and with a bad response to TMZ treatment.

Keywords: GMFG; gliomas; immune; prognosis; temozolomide.

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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
Glia maturation factor-γ (GMFG) expression in gliomas. (A) Transcripts of GMFG in pan-cancers in the GEPIA platform; (B) alterations to mRNA and protein levels of GMFG in different types of cancers in Oncomine; (C) relative mRNA level of GMFG in non-tumor brain tissues (NBT) and gliomas tissues from Gravendeel, Rembrandt, Gill, and Murat datasets; (D,E) immunohistochemistry (IHC) staining of GMFG in NBT and gliomas tissues. **P < 0.01, ***P < 0.001, ns, no significance.
FIGURE 2
FIGURE 2
Glia maturation factor-γ expression correlated with malignancy of gliomas. (A–D) TCGA, CGGA, Gravendeel, and Rembrandt were used to investigate GMFG expression in gliomas. All data were downloaded from GlioVis platform. (E,F) IHC staining of GMFG in lower grade gliomas (LGG) and glioblastoma (GBM); (G,H) GMFG expression in gliomas with different IDH and 1p19q status in CGGA and TCGA datasets; (I,J) gene sequencing of glioma tissues from our validation cohort. GMFG expression in gliomas with different IDH and 1p19q status. mut, mutant; wt, wild-type. *P < 0.05, **P < 0.01, ***P < 0.001, ns, no significance.
FIGURE 3
FIGURE 3
Glia maturation factor-γ expression associated with GBM subtypes. (A) GMFG expression in different subtypes of GBM in the TCGA, CGGA, Gravendeel, and Rembrandt datasets. CL, classical; ME, mesenchymal; PN, proneural. ***P < 0.001. (B) Accuracy of GMFG to predicting ME subtype as determined using ROC curves. ROC, receiver operating characteristic; AUC, area under the curve. (C) Spearman correlation method was employed to analyze the correlation coefficient between GMFG and mesenchymal-related genes in TCGA and CGGA.
FIGURE 4
FIGURE 4
GO functional enrichment of GMFG-related terms in gliomas. The top 100 genes that were positively correlated with GMFG (Spearman r > 0.50, P < 0.01) were downloaded from the cBioPortal platform (http://www.cbioportal.org/) based on TCGA-GBM. GO enrichment analysis were classified into three. (A) Biological process; (B) molecular function; (C) cellular component categories. (D) KEGG pathways prediction. (E) Protein–protein interaction networks were performed in Metascape (http://metascape.org/).
FIGURE 5
FIGURE 5
Glia maturation factor-γ correlated with immune cell infiltration in gliomas. Correlations between GMFG expression and stromal score (A) and immune score (B). Stromal and immune scores were calculated by using the ESTIMATE. (C) Correlation between GMFG expression and the immune infiltration levels in TIMER. (D–F) Gliomas single-cell sequencing datasets from the TISCH database were used to explore the association between GMFG expression and immune cell infiltration.
FIGURE 6
FIGURE 6
Association between GMFG expression and tumor-associated macrophages infiltration in gliomas. (A) We detected immune cells (CD11b+ and CD163+) infiltration in GBM and LGG samples using IHC staining, respectively. (B,C) Spearman correlation was employed to explore correlation between immune cells infiltration and GMFG expression. The IHC staining results were independently analyzed by two individuals.
FIGURE 7
FIGURE 7
High GMFG expression predicted a worse prognosis in gliomas. Kaplan–Meier curves were used to plot overall survival curves against optimal cutoff in TCGA, CGGA, Gravendeel, and Rembrandt datasets. The optimal cutoff was determined using GlioVis. HR, hazard ratio.
FIGURE 8
FIGURE 8
Glia maturation factor-γ associated with TMZ response of gliomas. (A) Association between GMFG expression and MGMT promoter methylation status. ***P < 0.001. (B–E) Correlation between GMFG expression and MGMT expression in TCGA, CGGA, Gravendeel, and Rembrandt datasets based on Spearman correlation analysis. (F,G) Effect of GMFG on the prognosis of patients with LGG and GBM with different MGMT promoter methylation status. HR, hazard ratio. ***P < 0.001, ns, no significance. (H,I) Effect of GMFG on the prognosis of gliomas patients who received chemotherapy at any time or radiotherapy only. AA, alkylating agent; IR, ion radiotherapy. **P < 0.01, ns, no significance.
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