Methylation status of TK1 correlated with immune infiltrates in prostate cancer

Abstract

TK1 is overexpressed in numerous cancers and is associated with to a poor prognosis. However, the relationship between methylation status of TK1 and Immune Infiltrates in Prostate Cancer (PCa) is unknown. The goal of this study was to use comprehensive bioinformatic analyses to elucidate the involvement relationship between methylation status of TK1 and Immune Infiltrates in PCa. TK1 mRNA expression and methylation data in PCa were investigated via GEPIA, TIMER, and UALCAN coupled with MEXPRESS data resources. We employed the LinkedOmics data resource to determine the signaling cascades linked to TK1 expression. Single-cell analysis was performed using the CancerSEA data resource. GeneMANIA and CancerSEA were used to analyze the correlation between TK1 and TK1 coexpressed genes. In addition, TIMER and TISIDB were adopted to assess tumor-invading immune cells and immunomodulators. CTD was utilized to detect the drugs acting on TK1. This study found that TK1 was overexpressed in PCa, and its contents were linked to tumor stage and prognosis. Genes co-expressed with TK1 were enriched in cascades involved in the ribosome, cell cycle, oxidative phosphorylation, DNA replication, oocyte meiosis, and the proteasome. The expression of TK1 along with its methylation status was found to be linked to tumor-invading immune cells, as well as PCa immunomodulators. We also examined the prospect of employing TK1 as a possible target for PCa therapy. This work provides the clinical value of TK1 hypermethylation in PCa and highlights new insights into its novel immunomodulatory functions.

Keywords: DNA methylation; immune infiltrates; prognostic biomarker; prostate cancer; thymidine kinase 1.

FIGURE 1

Overexpression of TK1 in PCa. (A) TK1 expression levels in various human malignancies were analyzed by TIMER. (B) UALCAN analyzed TK1 mRNA levels in tumor tissues and nontumorous tissues. (C) The expression of TK1 mRNA between different nodal metastasis statuses of PCa tissues was analyzed by UALCAN. (D) Differential protein expression of TK1 in tumor and nontumorous tissues in the HPA. (E) GEPIA analyzed high or low expression levels of TK1 in various malignant tumors.

FIGURE 2

Prognostic value as a result of TK1 in PCa patients. (A,B) GEPIA profiling showed that PCa patients with high TK1 expression were associated with poorer OS. (A) and PFS (B) relative to those with low TK1 expression.

FIGURE 3

DNA methylation level of TK1 in PCa. (A) UALCAN data resource showing promoter methylation levels of TK1 in normal and PCa tissues. (B) UALCAN data resource offering promoter methylation levels of TK1 in PCa tissues with different nodal metastasis statuses. (C) Relationship between TK1 expression and PCa and methylation around CpG islands and promoter regions.

FIGURE 4

Gene and functional enrichment analysis of TK1 coexpression. (A) Volcano map of TK1 coexpression in PCa according to the LinkedOmics data resource. (B,C) Heatmap of the top 50 genes positively (B) and negatively (C) linked to TK1 are shown. (D) Gene network associated with TK1, analysis by GeneMANIA. (E) Interaction network map between proteins encoded by TK1 genes plotted with STRING. (F) Single-cell analysis of the CancerSEA data resource indicates that TK1 is mainly involved in the cell cycle, DNA repair, and apoptosis. (G,H) TK1 coexpressed genes were annotated on LinkedOmics via Gene Ontology (GO) assessment (G) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis (H).

FIGURE 5

Single-cell analysis of the functional characteristics of TK1 in prostate cancer. (A) Correlation between TK1 and 14 cell functions. (B) The screened functional state with significant indigenous correlation with TK1.

FIGURE 6

Association of TK1 and E2Fs in PCa. (A) Molecular correlation analysis of TK1 and E2Fs. (B) Human expression levels of E2Fs in PCa from The Cancer Genome Atlas (TCGA) data resource were estimated by the ggplot2 R package (v3.3.3) algorithm. (*<0.05, **<0.01, ***<0.001).

FIGURE 7

Effect of immune cell invasion on TK1 expression in individuals with PCa. (A) Relationship between the invasion contents of 24 immune cell types and the expression profile of TK1. (B) Comparison of the most associated levels of immune cell invasion in the high and low TK1 expression groups, including eosinophils, Tcm, neutrophils, mast cells, Tgd, NK cells, Th2 cells, TRed cells, and NK CD56bright cells. (*<0.05, **<0.01, ***<0.001).

FIGURE 8

The relationship of the methylation status of TK1 with immune infiltration in PCa. (A) Relationship of the methylation status of TK1 with Th2 cells, Tregs, NK eosinophils, NK cells, neutrophils, Tcm, and Tgd in PCa available from the TISIDB data resource. (B) Relationship of the methylation status of TK1 with immunostimulator PCa available from the TISIDB data resource.

FIGURE 9

Drug response related to TK1 expression in PCa.