Deoxythymidylate Kinase (DTYMK) Participates in Cell Cycle Arrest to Promote Pancreatic Adenocarcinoma Progression Regulated by MiR-491-5p Through TP53 and is Associated with Tumor Immune Infiltration

Overview

Journal J Gastrointest Oncol

Date 2023 Jul 12

PMID 37435228

Authors

Wenguang Bao

Haiyan Yang

Shengsheng Zhou

Fengxiang Huang

Zhe Wei

Zhigang Peng

Affiliations

Soon will be listed here.

Abstract

Background: This study aimed to understand the mechanism of action of deoxythymidylate kinase (DTYMK) and its effect on the prognosis of patients with pancreatic cancer. So as to provide better reference value for improving the clinical management of pancreatic cancer patients.

Methods: First, The Cancer Genome Atlas (TCGA) database was employed to identify DTYMK as a differentially expressed gene and to further confirm its expression and its association with the prognosis of pancreatic adenocarcinoma (PAAD) patients. Furthermore, Cox Law of Return is used for multi factor analysis. By constructing a multi factor regression model, a nomogram is constructed according to the contribution of each influencing factor in the model to the outcome variables, The GeneMania and STRING databases served as the basis for investigating the protein-gene interaction network. Moreover, to understand the correlation between DTYMK and immune cells, the TIMER and TCGA databases were explored. Then, Gene Set Enrichment Analysis (GSEA) was performed to investigate potential mechanisms of action. TargetScan was used to identify the miRNAs binding to the 3'UTR of DTYMK mRNA, and starBase was used to verify a possible link between candidate miRNAs and DTYMK. In parallel, the expression of these potential miRNAs in PAAD and their correlation with prognosis was validated through the TCGA database.

Results: PAAD patients were observed to have high overall survival (OS), progression free interval (PFI), and disease-specific survival (DSS) with reduced DTYMK expression. Data from the TIMER database show that DTYMK expression inversely correlated with the infiltration levels of most immune cells. GSEA results suggested that DTYMK has a role in cell senescence, DNA repair, pyrimidine metabolism, MYC activation, TP53 control of cell cycle arrest, apoptosis, and the MAPK6/MAPK4 pathway, all of which might influence the biological processes of PAAD.

Conclusions: Reduced DTYMK expression may be considered a novel prognostic biomarker for PAAD patients, associated with improved OS, DSS, and PFI. Immune escape may play an important facilitative role. Moreover, we found that miR-491-5p may negatively regulate DTYMK and participate in cell cycle arrest through TP53 to promote pancreatic cancer progression.

Citing Articles

The Biological Behavior and Clinical Application Prospects of Deoxythymidine Kinase Gene in Tumors.

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PMID: 39420855 PMC: 11497513. DOI: 10.1177/15330338241265396.

Co-Targeting of DTYMK and PARP1 as a Potential Therapeutic Approach in Uveal Melanoma.

Ozieblo S, Mizera J, Gorska A, Krzyzinski M, Karpinski P, Markiewicz A Cells. 2024; 13(16.

PMID: 39195238 PMC: 11352547. DOI: 10.3390/cells13161348.

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