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

Abstract

Malignant tumors have become a significant risk factor for human mortality. Although there have been notable advancements in the treatment of tumors, patient prognosis remains poor. In recent years, gene diagnosis and gene therapy have brought great benefits to patients. Deoxythymidine kinase (DTYMK) is a highly promising biomarker, has been studied by many scholars, and plays a crucial role in the occurrence and development of various types of cancer. The abnormal expression of DTYMK is involved in tumor occurrence and development, and may also serve as a biomarker for tumor diagnosis, treatment, and prognosis. Several experimental studies have shown that DTYMK can impact tumor progression by regulating mechanisms such as cell cycle, tumor microenvironment, immune infiltration, and signaling pathways. Therefore, this article focuses on clarifying the mechanism of DTYMK in tumors and exploring its clinical application value to help patients prolong their survival cycle and improve their quality of life.

Keywords

deoxythymidine kinase (DTYMK)malignant tumors mechanism of action research progress application value

Introduction

Tumors are a type of disease that threatens human life and health.¹ According to cancer data statistics from China and the United States,² there were approximately 4820000 and 2370000 new cancer cases, as well as 3210000 and 640000 cancer deaths, respectively, in 2022. Imaging and laboratory tests are crucial indicators for diagnosing tumors,³ while pathological biopsy remains the “gold standard” for diagnosing the vast majority of tumors.⁴ For most solid tumors, surgery can be a viable treatment option in the early stages, providing a good prognosis for patients.⁵ However, when tumors are discovered, they are often in the advanced stage, losing the best opportunity for surgical treatment and resulting in poor survival prognosis. Therefore early screening and genetic diagnosis are crucial in the management of tumors.⁶ Tumor markers such as squamous cell carcinoma antigen (SCCA),⁷ alpha-fetoprotein (AFP),⁸ and carbohydrate antigen 125 (CA125)⁹ can assist in detecting squamous cell carcinoma, liver cancer, and ovarian cancer at an early stage, respectively.^6-9 With the advancements in medical technology, genetic technology has become instrumental in diagnosing and treating tumors.¹⁰ For instance, HER2 positive is used to determine the suitability of single-targeted therapy with trastuzumab for gastric cancer and breast cancer, which has significantly improved the survival and prognosis of tumor patients.^11,12

DTYMK¹³ is a nuclear-encoded thymidine kinase related to pyrimidine metabolism and can catalyze the phosphorylation of dTMP to dTDP biosynthesis, dTTP biosynthesis, and dUDP biosynthesis processes.¹⁴ dTTP is a vital raw material for DNA synthesis and replication,¹³ and DNA replication is a crucial process for the formation of tumors.¹⁵ Hence, DTYMK may participate in regulating the development of various tumors by affecting dTTP synthesis (Figure 1).

Figure 1.

The mechanism of DTYMK in pyrimidine metabolism (by Figdraw).

Recent studies have found that DTYMK is highly expressed in various types of cancer, including liver,¹⁶ lung,¹⁷ colorectal,¹⁸ and pancreatic cancer.¹⁹ High expression of DTYMK affects tumor growth, tumor immune microenvironment, and tumor progression.²⁰ Patients with high levels of DTYMK are more sensitive to platinum anti-tumor drugs such as oxaliplatin and may be a potential biomarker for tumor prognosis²¹ (Figure 2). Furthermore, DTYMK plays an essential role in maintaining the integrity of our genes and keeping our neurons healthy. A deficiency in DTYMK can lead to childhood onset, progressive microcephaly, developmental and epileptic encephalopathy, and neurodegeneration.^22,23 We will comprehensively describe the role and potential clinical applications of DTYMK in both tumors and other diseases.

Figure 2.

The mechanism of action of DTYMK in tumors (by Figdraw).

The Mechanism of Action of DTYMK

Nucleotides are essential molecules involved in various metabolic processes, and play a crucial role in the synthesis of RNA and DNA. They have multiple biological functions, primarily serving as building blocks for nucleotide synthesis.²⁴ The DTYMK gene belongs to the thymidine kinase protein family and is located at position 2q37 on chromosome 2. It can be found in the cytoplasm, nucleus, and mitochondria.¹⁴ CMPK is an important homolog of DTYMK.²⁵ Thymidine nucleotides can be synthesized through two pathways: the de novo pathway of dTMP and the salvage pathway of thymine and thymidine reuse. The de novo pathway is mainly responsible for cell replication.²⁶ DTYMK is an enzyme that helps in the formation of dTDP from dTMP during the biological synthesis of pyrimidine deoxyribonucleotides. dTDP is a key component in the formation of dTTP,¹³ which is essential for DNA synthesis. The process of DNA biosynthesis involves DNA replication, RNA reverse transcription into DNA, and DNA damage repair. DNA replication is a crucial step in the development of tumors as abnormal cell growth cannot occur without DNA replication.²⁷ DTYMK affects pyrimidine metabolism, which in turn interferes with DNA synthesis and regulates the formation of tumors to a certain extent.

The Role and Clinical Application of DTYMK in Human Tumors

DTYMK and Pan-Cancer

Pan-cancer refers to the analysis of multiple cancer types or subtypes in an integrated manner. The goal is to identify common genes, pathways, biomarkers, or other features across multiple cancers, and analyze the differences and similarities among various cancer types. This information can be used to advance research on tumor biology and provide the basis for clinical diagnosis, treatment, and prognosis of tumors.^28,29 The expression of DTYMK is associated with many types of tumors.

The Expression of DTYMK in Pan-Cancer

The researchers have discovered that^17,20,30,31 DTYMK is overexpressed in various types of tumors, including bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma (CESC), and others. However, it is down-regulated in Kidney Chromophobe (KICH).²⁰

The Diagnostic Role of DTYMK in Pan-Cancer

The expression level of DTYMK is correlated with clinicopathological features such as tumor stage. In ACC and KICH tumors, the expression of DTYMK increases in the IV stage,³¹ which is correlated with the T stage in ACC and LUAD tumors, and with the N stage in LUAD tumors. It is associated with the M stage in ACC, KIRC, and LUAD tumors, and with the TNM stage in ACC-KIRC, LIHC, LUAD, and LUSC. ROC curve analysis results showed that the AUC value was greater than 0.80 in BLCA, BRCA, CKIRP, LUAD, KICH, and other tumors, indicating that DTYMK is a potential biomarker for tumor diagnosis.²⁰

The Therapeutic Effect of DTYMK in Pan-Cancer

DTYMK has a strong correlation with dendritic cells, B cells, neutrophils, CD4 + T cells, macrophages, and CD8 + T cells in most tumors. In LUAD, it shows a negative correlation with infiltration levels of B cells, CD8 + T cells, CD4 + T cells, macrophages, and dendritic cells, while in LIHC, it is positively linked with infiltration levels of B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells,^20,30,31 indicating thindicatingntial distribution of DTYMK in different stages, immune and molecular subtypes.³¹ DTYMK expression is associated with tumor immunity, as well as immune checkpoint (ICI), tumor mutation burden (TMB),³² and microsatellite instability (MSI)³³ status. DTYMK expression is associated with one or more immune checkpoints. In tumors such as LUAD and KICH, the expression level of DTYMK is positively correlated with TMB, and in tumors such as LIHC and KIRC, the expression level of DTYMK is positively correlated with MSI status. DTYMK is closely related to the tumor immune microenvironment and may be involved in tumor immunotherapy.³⁰ It is a potential target for tumor treatment and is expected to guide patient treatment.

The Prognostic Role of DTYMK in Pan-Cancer

Researchers have found that^20,30,31 in various tumors, patients with high expression of DTYMK often have poor overall survival (OS), disease-specific survival (DSS), etc The poor prognosis of patients may be significantly related to cell cycle, DNA damage, DNA repair, invasion, epithelial-mesenchymal transition (EMT), and proliferation.^20,31 Knocking down DTYMK can inhibit cell migration, clone formation, and cell proliferation.²⁰ In addition, DTYMK co-expressed genes are involved in pyrimidine metabolism and T helper cell differentiation in LIHC and LUAD.³¹ DTYMK affects tumor growth by interfering with cell function, further affecting tumor prognosis.

DTYMK is a gene that gets activated more than usual in different types of tumors, and this can be a bad sign for the patient's recovery. It also seems to be related to how advanced the tumor is and how it affects the immune system's response. Moreover, DTYMK is associated with certain features such as ICI, TMB, and MSI, which can influence how fast the tumor grows by affecting the cancer cells’ behavior. For all these reasons, DTYMK could be a helpful tool for doctors to diagnose different types of cancer and predict how severe the disease is. Also, it might be a promising target for immunotherapy, which is a type of treatment that uses the body's immune system to fight cancer cells. With this information, clinicians can better develop personalized treatment plans and monitor the patient's progress.

DTYMK and Hepatocellular Carcinoma (HCC)

HCC is a frequently occurring malignant tumor worldwide.³⁴ Although the early diagnosis of HCC can be made through ultrasound examination and AFP serological evaluation,³⁵ these methods often lack accuracy due to low sensitivity and specificity.³⁶ There is a need to find biomarkers to diagnose and predict HCC urgently. DTYMK may be such a biomarker.

DTYMK Exhibits High Expression Levels in HCC

The researchers^21,37-41 analyzed databases, acquired HCC tissue samples, conducted experiments on liver cancer cell lines, and validated the datasets, protein, and RNA levels. They discovered that in comparison to normal tissues, DTYMK demonstrated elevated expression in HCC.

The Diagnostic Role of DTYMK in HCC

Establishing ROC curves with AUC values greater than 0.5 indicates that the expression level of DTYMK has a certain value in diagnosing HCC.^37,38 The expression level of DTYMK may be related to HCC grading, staging, and lymph node status, and is positively correlated with the size of HCC, disease staging, and pathological grading.^37,38,42 Late-stage tumors, especially stages III and IV, are significantly correlated with high expression levels of DTYMK, with shorter tumor doubling time, vascular infiltration, and fibrosis being more severe.⁴⁰ Further experimental verification shows that DTYMK expression can increase with higher HCC grading and increases during TMN staging I-IV and pathological I-III stages.³⁹ In addition, the expression level of DTYMK is also related to lymph node metastasis. As lymph node metastasis increases, the expression level of DTYMK also increases.⁴² The expression level of DTYMK may help diagnose the malignancy of HCC.

Application Value of DTYMK in HCC Therapy

It has been found that the therapeutic effect of DTYMK in HCC may be related to the functional status of tumor cells. Through GO enrichment and KEGG pathway analysis, it was observed that DTYMK is positively correlated with DNA biosynthesis, cell cycle, and acid metabolism pathways.³⁹ Silencing DTYMK leads to a decrease in tumor formation ability,⁴³ cell proliferation, and cloning ability, which is manifested as inhibition of Hep3B and Huh7 cell proliferation. The addition of DTYMK catalytic product dTDP restores the growth of inhibited tumors. After knocking down DTYMK, the levels of proteins CDK2 and CDK4, which are involved in the G0/G1 and S phases of the cell cycle, as well as Cyclin A2 and CyclinD1, were found to be significantly reduced..²¹ DTYMK knockdown models using RNAi methods and animal models resulted in a reduction of approximately 2 times in cell numbers.⁴¹ The cell cycle is also inhibited, manifested by prolonged G0/G1 phase and shortened S phase.^21,38,40,42 Transwell results also showed a decrease in cell migration and invasion rates.³⁸ The above experimental results indicate that knocking out DTYMK inhibits HCC growth.

The therapeutic effect of DTYMK in HCC may be related to its ability to affect the immune infiltration in tumor cells and the tumor immune microenvironment. TISIDB verified the correlation between immune-related molecules in HCC tissue samples and found that DTYMK is associated with 8 immune stimulatory molecules and 5 immune suppressive factors. Among them, the expression level of DTYMK is directly proportional to tumor purity (r = 0.139, P < .05) and positively correlated with CD + 4 T cells, B cells, macrophages, neutrophils, etc but not significantly with CD8 + T cells.^37,39 Additionally, DTYMK is also associated with the infiltration of M2 macrophages in HCC (r = 0.262, P < .001). The resistance of oxaliplatin in HCC mainly promotes the expression of CCL5 and the proliferation of tumor cells, thereby increasing the infiltration of CD163+ M2-type TAMs in the tumor immune microenvironment.²¹

The level of DTYMK expression in HCC may have a therapeutic effect related to its targeted regulatory effect, platinum sensitivity, and drug resistance. MiR-148b-3p is an upstream regulatory factor of DTYMK, which can regulate its expression level. In HCC, both DTYMK expression and dTTP concentration increase. Overexpression of miR-148b-3p leads to a decrease in dTTP and DTYMK levels, thereby inhibiting the growth of HCC. Therefore, the miR-148b-3p/DTYMK axis may be an important target for the treatment of HCC patients.⁴¹ By integrating the interaction between circRNA miRNA and miRNA mRNA, establishing a circRNA miRNA mRNA regulatory network, and discovering that when hsa_Cir_0002003 is in silenced, DTYMK and other genes targeted by hsa-miR-1343-3p were significantly downregulated in HCC cells. Therefore, targeting the hsa_Cir_0002003/has miR-1343-3p/STMN1 regulatory axis may be an effective therapeutic target for HCC patients.⁴⁰ Chemotherapy is a common treatment for advanced tumors, and sorafenib⁴⁴ is a novel multi-targeted anti-tumor drug. Data shows that it can significantly improve patient prognosis.⁴⁵ Knocking down DTYMK can reduce resistance to chemotherapy drugs such as sorafenib and oxaliplatin.^21,39,43 The resistance of HCC to oxaliplatin may be due to the competitive binding of miR-378a-3p with DTYMK through the MAPKAPK2/p-HSP27/NF κB pathway, which mediates to maintain MAPKAPK2 expression.²¹ Yang's research confirms that miR-378a-3p may play an important role in cancer chemotherapy resistance.⁴⁶ High expression levels of DTYMK are sensitive to 12/18 chemotherapy drugs, with lower IC50.³⁹ Overall, DTYMK expression levels are related to chemotherapy drug sensitivity and resistance, which can help guide clinical students to develop personalized treatment plans. It has good clinical application prospects.

The Prognostic Value of DTYMK in HCC

Patients who have high expression levels of DTYMK are likely to have a poor prognosis and experience worse OS and DSS.^{21,36,39-41,43} This could be due to the upregulation of the dTTP biosynthesis pathway in pyrimidine metabolism.⁴³ The prognosis of HCC patients could be associated with competitive endogenous RNA (ceRNA) networks. AP003469.4 is a type of long-chain non-coding RNA (LncRNA) that is highly expressed in HCC, with an AUC of 0.9048 and is linked to poor OS and DFS in HCC patients. It can be considered a risk factor for poor prognosis in HCC patients. This type of RNA interacts with miRNAs, which can affect the expression of miRNA target genes. In tumors, lncRNA regulates gene expression in the ceRNA network through competitive endogenous miRNA regulation.⁴⁷ DTYMK is a highly expressed differentially expressed gene (DEG) in the differential analysis of target genes. Fan et al created an AP003469.4- miRNA- mRNA- ceRNA network and risk model based on DTYMK. The univariate Cox regression analysis and Cox regression analysis both showed that DTYMK is an independent risk factor for poor prognosis in HCC patients. This is likely related to the MAPK signaling pathway, cell cycle, DNA replication, mTOR signaling pathway, and other factors.³⁷ DTYMK can affect the occurrence of HCC and potentially serve as a biomarker for predicting the prognosis of HCC patients.

In summary, DTYMK is highly expressed in HCC and significantly correlated with the clinical and pathological status of HCC, affecting grading, staging, and lymph node status. The expression level of DTYMK is also related to the sensitivity and resistance of tumor chemotherapy drugs. It can interfere with the functional status of tumor cells, immune infiltration, tumor immune microenvironment, and other factors that can regulate the progression of HCC. High expression of DTYMK is associated with poor prognosis in HCC patients, and poor OS. As a hub gene in the ceRNA network, DTYMK is differentially expressed in pyrimidine metabolism, DNA replication, and other factors, affecting the prognosis of HCC patients. DTYMK may be a potential drug target for HCC treatment, which can guide clinical doctors in formulating personalized treatment plans and has the potential to predict the prognosis of liver cancer patients. It is a potential biomarker for predicting prognosis.

DTYMK and Lung Cancer

Lung cancer is a type of cancer that originates from the trachea, bronchial mucosa, or glands of the lungs.⁴⁸ Although lung cancer is not contagious,⁴⁹ it can be genetically inherited. Lung cancer has a high incidence and mortality rate globally. Although there has been a decline in recent years, it still ranks first among men and third among women in terms of incidence rate and mortality of malignant tumors.⁵⁰ DTYMK is closely related to lung cancer and is a biomarker that can predict the prognosis of lung cancer.

DTYMK Exhibits High Expression Levels in Lung Cancer

After analyzing databases, collecting tissue samples from patients, and conducting cell experiments, researchers found that^17,28,51-53 DTYMK is expressed at higher levels in individuals with lung cancer compared to normal ones.

The Diagnostic Role of DTYMK in Lung Cancer

The upregulation of DTYMK is related to adverse pathological staging and TNM staging.^17,30 ROC curve analysis showed that the AUC value of DTYMK was 0.914, with a 95% CI of 0.886–0.943,¹⁷ indicating that DTYMK is a biomarker for the diagnosis of lung cancer.

The Therapeutic Effect of DTYMK in Lung Cancer

The role of DTYMK in lung cancer may be related to the functional status of tumor cells. The expression level of DTYMK is associated with cell proliferation, cell cycle, cell migration, and cell invasion.^17,30,51 By knocking down DTYMK, the ability of cells to proliferate, migrate, and invade is suppressed, and the cell cycle arrest. Additionally, the expression level of DTYMK is closely linked to DNA damage, DNA repair, oxidative phosphorylation, focal adhesion factors, and chemokine signaling pathways.¹⁷ The PI3K-AKT pathway is an intracellular signal transduction pathway that responds to extracellular signals, promoting metabolism, proliferation, cell survival, growth, and angiogenesis.⁵⁴ By inhibiting DTYMK, the activity of the PI3 K/AKT signaling pathway is also suppressed, which can further inhibit tumor growth.³⁰ Knocking down DTYMK can also inhibit the signal transduction and transcription activating factor 3 (STAT3) activation pathways, thus achieving the goal of inhibiting cell growth vitality, migration, and invasion.⁵³ This indicates that DTYMK affects tumor growth by affecting the PI3 K/AKT pathway and STAT3 signaling pathway, and it can be used as a detection gene for lung adenocarcinoma (LUAD) and a prognostic biomarker for lung cancer patients.

The expression level of DTYMK in lung cancer may have a therapeutic effect that is linked to the infiltration level of tumor-infiltrating immune cells (TIICs) and sensitivity to cisplatin. A high expression of DTYMK results in increased infiltration of TIICs, which is positively correlated with the abundance of 22 types of human immune cells.¹⁷ DTYMK is closely related to immune cells and plays a crucial role in lung cancer immunity. Additionally, cancer stem cells (CSCs) share similar phenotypes and functions with normal stem cells or progenitor cells located in the same tissue and have strong carcinogenicity, tumor metastasis, and drug resistance formation characteristics that are closely related to the difficulty of tumor treatment.^55,56 Lowering the levels of DTYMK can increase the sensitivity of LUAD to cisplatin, which may be due to its association with CSCs.³⁰ Therefore, DTYMK could be a potential therapeutic target for lung cancer.

Metabolic reprogramming is an important marker of cancer.⁵⁷ Abnormal proliferation of tumor cells requires energy maintenance, increased glucose intake, and the use of glycolysis to promote abnormal cell proliferation.⁵⁸ In addition to glucose metabolism disorders, pyrimidine metabolism also affects the development process of tumors. High levels of DTYMK increase the rate of pyrimidine metabolism, promote uncontrolled cell proliferation, and affect the normal function of immune cells. LKB1⁵⁹ is an important tumor suppressor gene that coordinates cell growth, polarity, motility, and metabolism. Loss or mutation of LKB1 is manifested as a change in dTTP metabolism in lung cancer cells and significantly disrupts intracellular dTTP synthesis. KRAS-driven LKB1 mutations are a new target for lung cancer treatment, and LKB1 mutations or deletions may be associated with poor tumor prognosis. Both LKB1 and DTYMK are involved in metabolic re-coding. Knocking down DTYMK can significantly inhibit the generation of LKB1-deficient cell lines. Based on knocking down DTYMK, overexpression of DTYMK can restore the growth of LKB1 deficient cell lines. DTYMK levels may be a potential therapeutic target for LKB1-mutated human cancer.⁵¹

DTYMK is Associated With the Prognosis of Lung Cancer

It has been observed that patients with LUAD who have higher expression levels of DTYMK tend to have poorer OS, DSS, and progression-free survival (PFS). The OS rate of LUAD patients is significantly correlated with their T, N, M staging, and pathological staging.^17,30 Low DNA methylation,⁶⁰ DNA amplification,⁶¹ and gene mutations⁶² often result in high expression levels of oncogenes. Compared to normal tissue, cancer tissue has lower levels of DNA methylation, and DNA amplification is another critical factor in the activation of cancer cells. The TP53 gene plays a crucial role in regulating multiple signaling pathways in cancer cells.⁶³ Loss of TP53 function can result in uncontrolled pyrimidine synthesis, and the enzyme DTYMK, which is responsible for rate-limiting pyrimidine metabolism, is highly expressed in TP53 mutant cancers. It has been observed that high expression of DTYMK in lung cancer cells may be linked to low DNA methylation, DNA amplification, and TP53 mutations. According to Kaplan Meier survival analysis, pyrimidine metabolism rate-limiting enzymes, including DTYMK, are associated with a poor prognosis for cancer patients.⁵² Therefore, DTYMK is a highly valuable biomarker for predicting the prognosis of lung cancer patients.

DTYMK is highly expressed in lung cancer tissue and is linked to poor patient prognosis and tumor staging. In lung cancer, it mainly affects the tumor progression process by impacting metabolic re-coding, glycolysis pathways, DNA replication, DNA repair, DNA methylation, TP53 mutations, RNA degradation, and tumor immune microenvironment, among others. It also plays a role in regulating tumor cell proliferation, cell cycle, cell migration, and cell invasion, and helps in guiding patients with LKB1 deficiency and TP53 mutations in their medication. DTYMK is considered a promising biomarker for predicting the prognosis of lung cancer patients.

DTYMK and Pancreatic Cancer

Pancreatic cancer is a type of malignant tumor that originates from the pancreatic duct epithelium and acini,⁶⁴ featuring rapid development and strong invasiveness. It is often referred to as the “king of cancer”.⁶⁵ Patients diagnosed with pancreatic cancer have a very poor prognosis, with an overall five-year survival rate of less than 7%.⁶⁶ Those who receive surgical treatment have a five-year survival rate of less than 20%.⁶⁷ Therefore, it is essential to identify biomarkers that can predict the occurrence and recurrence of pancreatic cancer.

The expression of DTYMK is found to be increased in pancreatic cancer.¹⁹ ROC curve was constructed to determine the diagnostic role of DTYMK, and it was found that the AUC was 0.667. Moreover, the therapeutic effect of DTYMK in pancreatic cancer may be associated with the tumor's biological function. Cell senescence is a state of terminal cell cycle arrest,⁶⁸ which can be promoted by DNA damage, MAPK signal transduction, cell cycle arrest, and so on. This can lead to metabolic reprogramming and senescence-related secretion phenotypes and changes in the structure and morphology of tumor cells.^69,70 DTYMK may be involved in cell aging, DNA repair, pyrimidine metabolism, MYC activation, TP53 mutation, and other processes. By regulating the cell cycle, cell apoptosis, and MAPK6/MAPK4 pathway, DTYMK can inhibit DNA damage repair and promote cell aging, as well as inhibit tumor cell growth.¹⁹ DTYMK may also be involved in regulating the immune microenvironment and affecting the process of tumor occurrence and development. Immunological analysis shows that DTYMK is negatively correlated with dendritic cell infiltration levels and positively correlated with neutrophils, CD4 + T cells, CD8 + T cells, and B cells, indicating that DTYMK expression may be related to immune infiltration of PAAD tumor cells,⁷¹ leading to immune escape in the immune tumor microenvironment and uncontrolled tumor growth.⁷² Patients with low expression of DTYMK have better OS, PFI, and DSS compared to those with high expression, indicating that the expression level of DTYMK is related to the prognosis of PAAD patients.¹⁸ DTYMK can serve as a biomarker for predicting the prognosis of PAAD disease.

DTYMK and Colorectal Cancer

Colorectal cancer is a common type of cancer that affects the digestive system. Blood in the stool⁷³ is the primary symptom of colon cancer and is usually the earliest and most common sign. CEA can help determine the prognosis and likelihood of recurrence,⁷⁴ but it is not always specific to the cancer and can appear in other tumors.⁷⁵ Surgical removal of the cancer is the preferred treatment, but the 5-year survival rate is only around 50%,⁷⁶ with a high recurrence rate being the main cause of failure. It is essential to monitor the patient's prognosis closely.

The expression of DTYMK is increased in colon adenocarcinoma, which is associated with poor OS in patients.¹⁸ In tumors, multiple drug resistance is caused by cell apoptosis and escape,⁷⁷ crucial mechanisms for tumor growth and drug resistance. MSI⁷⁸ is also an important factor in colorectal cancer (CRC) as it has immunogenicity, enhanced mutation, and leads to a large number of lymphocyte infiltration. MSI in CRC is characterized by high expression or deletion of one or more Mismatch Repair (MMR) proteins, CRC is due to germline mutations in DNA MMR genes MSH2, MSH6, or MLH1.⁷⁹ The protein required for MMR is encoded by PMS2.⁸⁰ Aloliqi's study found a correlation between DTYMK H-score and high expression of PSM2 and MSH2, indicating that DTYMK is co-expressed with PMS2 and MSH2 in CRC patients and has a synergistic effect, thereby affecting CRC resistance and progression.¹⁸ In the chemotherapy regimen for colorectal cancer, 5-fluorouracil (5-FU) is one of the commonly used standard drugs.⁸¹ High expression of DTYMK was found in 5-FU resistant CRC cell lines. Knocking out genes involved in thymidine biosynthesis can make cells sensitive to 5-FU, and knocking out DTYMK can significantly reduce IC50.^82,83 DTYMK may be related to CRC cell resistance, and it is suggested that it may guide clinical medication and serve as a predictive biomarker for the survival prognosis of colorectal cancer patients.

DTYMK and Other Tumors

DTYMK is a gene that has been found to have good predictive value in various types of tumors. It can also guide treatment decisions and predict prognosis in some other types of tumors. The expression level of DTYMK is related to the proliferation of melanoma cells and anti-tumor immunity. In vitro studies have shown that DTYMK mRNA is differentially expressed, and DTYMK cfRNA can be used to diagnose melanoma and monitor disease progression.⁸⁴ DTYMK is also an important gene in squamous cell carcinoma (cSCC), with AUC > 0.8 indicating strong predictive ability. Additionally, DTYMK is highly enriched in the KEGG pyrimidine metabolism pathway and can serve as a biomarker for predicting survival prognosis in cSCC.⁸⁵

DTYMK and Non-Tumor Diseases

The mechanism of action of DTYMK in tumors has been studied and reported by many scholars.^22,23 It has also been discovered in some rare diseases such as DNA mitochondrial depletion syndrome (MDDS),⁸⁶ which is a serious pediatric disease that is characterized by muscle weakness, progressive encephalomyopathy, deafness, and other symptoms. Unfortunately, due to the lack of specific biochemical indicators, it often leads to missed diagnosis, misdiagnosis, and delayed treatment. Researchers have found through family case analysis that DTYMK may be involved in the mitochondrial nucleotide rescue pathway. Its deletion or mutation leads to impaired generation of dTTP, which is an essential component of DNA synthesis, and this, in turn, leads to MDDS.⁸⁷ Through experiments with zebrafish, Frisk²³ found that DTYMK plays an important role in neural development. DTYMK mutations are associated with congenital defects and severe neurodegenerative diseases. This is consistent with the results of Vanoelen's study, which used zebrafish to verify the effects of DTYMK on maintaining gene integrity and neuronal survival.²² It indicates that DTYMK plays a crucial role in maintaining gene integrity and neuronal survival.

Discussion

DTYMK is a catalytic thymidine nucleotide synthesis kinase that catalyzes the formation of dTDP from dTMP.¹⁴ dTDP is the main substance in dTTP formation, and dTTP is an important substance in DNA synthesis,¹³ which includes DNA replication, DNA damage repair, etc Therefore, DTYMK may be involved in the DNA synthesis process, and DNA replication is a marker of abnormal tumor proliferation¹⁵ Many scholars have found that DTYMK is highly expressed in many tumors.³⁰ High expression levels of DTYMK promote tumor proliferation by affecting pyrimidine metabolism, cell cycle, cell proliferation, cell migration, and invasion ability. Moreover, cancer patients with high expression levels of DTYMK tend to have poorer prognosis, indicating that DTYMK may be a biomarker for predicting the survival prognosis of cancer patients. The immune system is a natural function of the body that recognizes foreign substances and eliminates them to maintain stability.⁸⁸ The tumor microenvironment⁸⁹ consists of tumor cells, host cells, and the secretion products of corresponding cells, such as cytokines, chemokines, and extracellular matrix components. This environment is like the “soil” for tumor survival. Tumor growth and metastasis depend on the immune microenvironment, which is similar to the relationship between seeds and soil.⁹⁰ Angiogenesis is essential for tumor growth and metastasis.⁹¹ The immune cells in the tumor microenvironment can stimulate the body to produce specific anti-tumor immune responses. They can also clear abnormal cells and eliminate abnormal tumor cells through immune monitoring functions, which play a crucial role in anti-cancer immunotherapy.⁹² Tumor immune escape⁹³ can limit the immune system's ability to eliminate tumor cells, leading to their abnormal proliferation and increased malignancy, which ultimately results in systemic metastasis. To overcome this, tumor immunotherapy⁹⁴ is a popular treatment method that activates the immune cells in the body, enhances the body's immune response, specifically clears small tumor lesions, and inhibits tumor proliferation. This method is widely used for the treatment of various malignant tumors, and it is effective in increasing both patient survival prognosis and PFS and OS. Researchers have discovered that DTYMK can affect the tumor immune microenvironment, and patients with high levels of DTYMK are more sensitive to tumor immune drugs. As Guo et al³⁹ found in their study, DTYMK expression is associated with 8 immunostimulatory molecules and 5 immunosuppressive molecules, with high DTYMK expression being more sensitive to 12 out of 18 chemotherapy drugs. In recent years, the application of tumor immunotherapy has benefited many cancer patients. PD-1/PD-L1 inhibitors are one of the commonly used tumor immunotherapy drugs,^95,96 closely related to the tumor microenvironment. PD-L1 can be expressed in macrophages, dendritic cells, as well as T cells, NK cells, and B cells.⁹⁷ PD1/PD-L1 inhibitors are more sensitive and effective in patients with high PD-1/PD-L1 expression.⁹⁸ Therefore, DTYMK may be a potential target for immunotherapy, and clinical doctors can develop personalized treatment plans based on the level of DTYMK, bringing greater benefits to tumor patients (Table 1).

Table 1.

Summary of DTYMK's Role in Tumors

	Expression	High
HCC	Prognosis	High expression levels of DTYMK are associated with poor OS, DSS, and pyrimidine metabolism, DNA replication, and other factors.
	Diagnose	The AUC value of the ROC curve is greater than 0.5, which may be related to the grading, staging, lymph node status of HCC, and positively correlated with the size, disease staging, and pathological grading of HCC.
	Therapy	The high expression of DTYMK may be related to the functional status of tumor cells; It is related to its ability to affect tumor cell immune infiltration and tumor immune microenvironment; It is related to its targeted regulatory effect, platinum sensitivity, and drug resistance.
Lung cancer	Prognosis	High expression levels of DTYMK are associated with poorer OS, DSS, and PFS, while OS is significantly correlated with its T, N, M staging, and pathological staging. Low DNA methylation, DNA amplification, and TP53 gene mutations can lead to an increase in DTYMK levels.
	Diagnose	The high expression of DTYMK is related to poor pathological staging and TNM staging. ROC curve analysis showed that the AUC value of DTYMK was 0.914, which has diagnostic value.
	Therapy	The role of DTYMK in cancer may be related to the functional status of tumor cells; May be related to the infiltration level of TIIC and sensitivity to cisplatin; It may also be a potential therapeutic target for human cancer with LKB1 mutations
Pancreatic cancer	Prognosis	Patients with high expression of DTYMK have poorer OS, PFI, and DSS.
	Diagnose	Constructing the ROC curve, it was found that the AUC was 0.667, which has certain diagnostic value.
	Therapy	It may be involved in processes such as cell aging, DNA repair, pyrimidine metabolism, MYC activation, TP53 mutation, etc; It is also related to the immune microenvironment in the process of tumor occurrence and development.
Colorectal cancer	Prognosis	Patients with high expression of DTYMK have poorer OS and PFI
	Diagnose	DTYMK is related to patient age, tumor staging, etc
	Therapy	The expression level of DTYMK may be related to cell apoptosis escape, microsatellite instability, and 5-FU resistance.

Although the mechanism of DTYMK in liver cancer, lung cancer, pancreatic cancer, colorectal cancer, and other tumors has been reported by many scholars, the mechanism of DTYMK in other tumors has not been clarified, such as breast cancer, nasopharyngeal cancer, and so on. In addition, there are few reports on the clinical application research data of DTYMK. Therefore, further clinical trials and experimental verification of DTYMK's mechanism of action in other tumors are needed in the future to better elucidate the mechanism of action and clinical value of DTYMK in tumors, bring greater benefits to patients, prolong their survival life, and improve their survival treatment.

Conclusion

In summary, DTYMK is significantly overexpressed in many malignant tumors, and individuals with high DTYMK expression often have poor prognosis. Patients with high DTYMK expression are more sensitive to tumor immunotherapy drugs. Therefore, DTYMK may be a biomarker for predicting the prognosis of tumor patients, and it could also be a potential target for immunotherapy.

Footnotes

Abbreviations

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (No. 82360540); Natural Science Foundation of Guangxi Zhuang Autonomous Region (No. 2023JJA140882); Guangxi Medical and Health Key Research Project (No. S2021104); “Hubei Chen Xiaoping Science and Technology Development Foundation” 2023 Cancer prevention research Huai ear special fund project (No. CXPJJH123003-039).

ORCID iD

Jiayu Zheng

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