Arachidonate lipoxygenases 5 is a novel prognostic biomarker and correlates with high tumor immune infiltration in low-grade glioma

Abstract

Objective: To investigate the prognostic value of arachidonate lipoxygenases 5 (ALOX5) expression and methylation, and explore the immune functions of arachidonate lipoxygenases 5 expression in low-grade glioma (LGG). Materials and Methods: Using efficient bioinformatics approaches, the differential expression of arachidonate lipoxygenases 5 and the association of its expression with clinicopathological characteristics were evaluated. Then, we analyzed the prognostic significance of arachidonate lipoxygenases 5 expression and its methylation level followed by immune cell infiltration analysis. The functional enrichment analysis was conducted to determine the possible regulatory pathways of arachidonate lipoxygenases 5 in low-grade glioma. Finally, the drug sensitivity analysis was performed to explore the correlation between arachidonate lipoxygenases 5 expression and chemotherapeutic drugs. Results: arachidonate lipoxygenases 5 mRNA expression was increased in low-grade glioma and its expression had a notable relation with age and subtype (p < 0.05). The elevated mRNA level of arachidonate lipoxygenases 5 could independently predict the disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI) (p < 0.05). Besides, arachidonate lipoxygenases 5 expression was negatively correlated with its methylation level and the arachidonate lipoxygenases 5 hypomethylation led to a worse prognosis (p < 0.05). The arachidonate lipoxygenases 5 expression also showed a positive connection with immune cells, while low-grade glioma patients with higher immune cell infiltration had poor survival probability (p < 0.05). Further, arachidonate lipoxygenases 5 might be involved in immune- and inflammation-related pathways. Importantly, arachidonate lipoxygenases 5 expression was negatively related to drug sensitivity. Conclusion: arachidonate lipoxygenases 5 might be a promising biomarker, and it probably occupies a vital role in immune cell infiltration in low-grade glioma.

Keywords: arachidonate lipoxygenases 5 expression; immune cell infiltration; low-grade glioma; methylation; prognosis.

FIGURE 1

ALOX5 gene expression profile. (A) The ALOX5 gene expression in various cancers. (B) The higher ALOX5 expression in low grade glioma (LGG). (C) The protein level of ALOX5 in LGG and normal tissues by immunohistochemistry analysis. (D) The correlation between ALOX5 expression and clinicopathological characteristics.

FIGURE 2

The association of ALOX5 expression with prognosis in low-grade glioma using the TCGA-LGG data. (A) High ALOX5 expression had no remarkable effect on DFI. High ALOX5 expression led to worse (B) DSS, (C) OS, and (D) PFI. DFI, disease-free interval; OS, overall survival; PFI, progression-free interval; HR, hazard ratio.

FIGURE 3

The predictive value of ALOX5 in low-grade glioma based on the TCGA-LGG data. The significance of ALOX5 in distinguishing the (A) DFI, (B) DSS, (C) OS, and (D) PFI statuses. DFI, disease-free interval; DSS, disease-specific survival; OS, overall survival; PFI, progression-free interval. AUC, area under the curve; 95% CI, 95% confidence interval.

FIGURE 4

The prognostic value of ALOX5 gene in CGGA-LGG data. (A) Patients with high ALOX5 gene expression had poor OS. (B) ALOX5 expression presented satisfactory performance in predicting the OS status. OS, overall survival; AUC, area under the curve; 95% CI, 95% confidence interval; HR, hazard ratio.

FIGURE 5

Nomogram construction and evaluation based on the multivariate Cox regression analysis results using the TCGA-LGG data. Nomogram was generated in terms of (A) disease-specific survival; (B) overall survival, and (C) progression-free interval.

FIGURE 6

Nomogram construction and evaluation based on the multivariate Cox regression analysis results using the CGGA-LGG data.

FIGURE 7

The ALOX5 methylation analysis in TCGA-LGG cohort. (A) The negative correlation between ALOX5 mRNA expression and its methylation level. (B) The prognostic value of the 14 methylated sites of ALOX5. FDR, false discover rate; HR, hazard ratio.

FIGURE 8

The immune cell infiltration analysis using ESTIMAE algorithm in TCGA-LGG data. The positive association of ALOX5 expression with (A) Immune score, (B) Stromal score, and (C) Estimate score. The correlation between the (D) Immune score-, (E) Stromal score-, and (F) Estimate score-based groups, and sample survival. HR, hazard ratio.

FIGURE 9

Immune cell infiltration analysis using TIMER algorithm. (A) The association of ALOX5 expression with several immune cells including B cell, CD8 + T cell, CD4 + T cell, macrophages, neutrophil, and dendritic cells. (B) The survival curves of the different immune cell groups.

FIGURE 10

The functional enrichment analysis of the significant differentially expressed genes (DEGs). (A) The volcano plot exhibiting all the DEGs between low-grade glioma and normal groups. (B) The heat map showing the top 50 DEGs. The (C) BP, (D) CC, (E) MF, and (F) KEGG of the significant DEGs. BP, biological process; CC, cellular component; MF, molecular function; KEGG, Kyoto Encyclopedia of Genes and Genomes.

FIGURE 11

Molecular characteristics of ALOX5. (A) GSEA enrichment showing the relative enriched pathways in high ALOX5 expression group. (B) Correlations between ALOX5 and immune activation-related genes. (C) Correlations between ALOX5 and immune checkpoint-related genes.

FIGURE 12

The negative correlation between ALOX5 expression and drug sensitivity based on GDSC and CTRP in the GSCA database.

FIGURE 13

The possible mechanism of ALOX5 involvement in low-grade glioma.