CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma

Abstract

Background: Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it's role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear.

Methods: In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells.

Results: As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p < 0.05). Meanwhile, high CDC6 expression was associated with poor overall survival (OS) in glioma patients, especially in different clinical subgroups. Furthermore, a univariate Cox analysis showed that high CDC6 expression was correlated with poor OS in glioma patients. Functional enrichment analysis indicated that CDC6 was mainly involved in pathways related to DNA transcription and cytokine activity, and Gene Set Enrichment Analysis (GSEA) revealed that MAPK pathway, P53 pathway and NF-κB pathway in cancer were differentially enriched in glioma patients with high CDC6 expression. Single-sample gene set enrichment analysis (ssGSEA) showed CDC6 expression in glioma was positively correlated with Th2 cells, Macrophages and Eosinophils, and negative correlations with plasmacytoid dendritic cells, CD8 T cells and NK CD56bright cells, suggesting its role in regulating tumor immunity. Finally, CCK8 assay, flow cytometry and transwell assays showed that silencing CDC6 could significantly inhibit proliferation, migration, invasion, and promoted apoptosis of U87 cells and U251 cells (p < 0.05).

Conclusion: In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.

Keywords: Biomarker; CDC6; Glioma; Immune infiltrates; Prognosis.

Fig. 1

The expression of CDC6 in different human cancers and its relationship with glioma prognosis. A PCA plot of the data showing no batch effect in the GSE104291 dataset. Red nodes represent the tumor cluster while blue nodes represent the normal cluster. B The volcano plots of DEGs in GSE104291. Red nodes represent upregulated genes, blue nodes represent downregulated genes, and gray indicates genes with no differential expression based on the criteria of p value < 0.05 and |log2 FC| > 1, respectively. C Wilcoxon rank sum test was used to analyze the differential expression of CDC6 in glioma tissues and normal tissues with the data of the GTEx database as controls. D CDC6 expression in TCGA tumors and normal tissues with the data of the GTEx database as controls. E Kaplan–Meier analysis of association between CDC6 expression and glioma prognosis in TCGA. F Kaplan–Meier analysis of association between CDC6 expression and glioma prognosis in CGGA. PCA, principal component analysis; DEGs, differentially expressed genes; log2 FC, log2 foldchange; TCGA, The Cancer Genome Atlas; GTEx, Genotype-Tissue Expression; CGGA, Chinese Glioma Genome Atlas. ns, p ≥ 0.05, *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 2

Transcriptional expression level and prognosis value of CDC6 in glioma from TCGA database. A-I The mRNA expression levels of CDC6 were analyzed in glioma patients according to (A) Age, (B) Gender, (C) Race, (D) IDH status, (E) 1p/19q codeletion, (F) WHO grade, (G-I) histological type, respectively. J-O Overall survival analysis towards the CDC6 expression was performed in subgroups of glioma patients: (J) Age: > 60, (K) Gender: Female, (L) primary therapy outcome: PD, (M) histological type: Glioblastoma, (N) IDH status: WT, (O) 1p/19q codeletion: non-codel. TCGA, The Cancer Genome Atlas; IDH, isocitrate dehydrogenase; WHO, World Health Organization; PD, progressive disease; WT, wild-type. ns, p ≥ 0.05, ***p < 0.001