LTF as a Potential Prognostic and Immunological Biomarker in Glioblastoma

Abstract

The lactoferrin (LTF) gene behaves like a tumor suppressor gene in diverse tumors, such as renal cancer, nasopharyngeal carcinoma and gastric cancer. However, the prognostic value of LTF expression in patients with glioblastoma remains unclear. In this study, the expression levels of LTF in patients with GBM were investigated in TCGA, GEPIA, CGGA and GEO database, and a survival analysis of LTF based on TCGA and CGGA was performed. Furthermore, the present study demonstrated the LTF gene co-expression, PPI network, KEGG/GO enrichment and immune cell infiltration analysis on TCGA and TIMER2.0 database. We found that LTF expression was significantly upregulated in GBM samples compared with normal samples and other glioma samples, and Kaplan-Meier analysis demonstrated that the overexpression of LTF were significantly associated with worse overall survival (OS) and 5-year OS in GBM patients (P < 0.05). KEGG/GO enrichment analysis demonstrated that functions of LTF concentrated in immune and inflammatory response and peptidase regulation (P < 0.05). Immune cell infiltration analysis presented that high LTF expression exhibited dysregulated immune infiltration (i.e., CD4 + T cells, neutrophils, macrophages, myeloid dendritic cells and cancer associated fibroblast). LTF was upregulated in tumors and correlated with worse OS in GBM patients, and LTF might function as an oncogene via inducing dysregulated immune infiltration in GBM.

Keywords: Glioblastoma; Immune cell infiltration; LTF; Survival.

Fig. 1

The expression level of LTF in all tumor tissues and cancer-side tissues based on TIMER 2.0 database(A) and GEPIA database(B) (*P < 0.05, **P < 0.01, ***P < 0. 001). The red cancer names denote the overexpression of LTF in this cancer, the green cancer names denote the low expression of LTF in this cancer, and black names represent no changes of LTF expression

Fig. 2

The comparison of LTF mRNA expression in normal and GBM samples base on TCGA and GEO database series including GSE4290(B), GSE116520(C) and GSE12657(D). ***p < 0.001, **p < 0.01, *p < 0.05 (t-test)

Fig. 3

The comparison of LTF mRNA expression base on CGGA database grouped by histology of brain tumor(A), IDH mutation status(B), WHO grade of brain tumor(C) and 1p/19q co-detection status of GBM(D). ***p < 0.001, **p < 0.01, *p < 0.05 (t-test)

Fig. 4

The LTF expression in single cells based on Single-Cell RNAseq analysis of diffuse neoplastic infiltrating cells in GBM (GSE84465). The Single-Cell RNAseq analysis of periphery tissue (A, B) and tumor tissue (C, D). The LTF expression level in different cells (B, D, E), red and grey colors denote the expression level of LTF high and low, respectively

Fig. 5

Mutation types and frequency of LTF in different data sets(A). Mutation sites of LTF(B). Mutation types and percentage of LTF in GBM (C)

Fig. 6

The overall survival (A, C) and 5-year overall survival (B, D) of GBM patients in TCGA and CGGA database grouped by the median of LTF expression

Fig. 7

A The top 10 most closely coexpressed genes of LTF based on TCGA-GBM dataset. B The PPI network of LTF in STRING

Fig. 8

GO and KEGG biological process enrichment of LTF interactive genes. Biological process(A), Cellular components(B), Molecular function(C) and KEGG(D)

Fig. 9

Correlation between LTF expression level and GBM immune cells infiltration level