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Published on: September 14, 2010
Expression Profile of Thymidine Kinase Genes in Cervical Squamous Cell Carcinoma Confirmed by Various Detection
Cai Xia Liang1, Ya Jun Pang2, Man Yu Chen2
1The First Clinical Medical School, Jinan University, Guangzhou 510632, Guangdong, China.
Background:
Thymidine kinases (TKs) are key enzymes involved in DNA synthesis and repair, with alterations in their expression associated with various cancers. Thymidine kinase 1 (TK1) and TK2 are cytosolic enzyme proteins that catalyze the addition of a gamma-phosphate group to thymidine. The existing literature on TK1 in cervical squamous cell carcinoma (CESC) fails to address the clinical role of TK1 overexpression and its possible molecular mechanism in CESC. The clinical significance of TK2 in CESC is also unknown. The objective was to explore the differential expression, clinical significance, and molecular mechanisms of TK1 and TK2 in CESC.
Methods:
The researchers collected global high-throughput data, extracted the expression levels of TK1 and TK2, and calculated the integrated standardized mean difference (SMD) and summarized receiver's operating characteristics (sROC) of TK1 or TK2 mRNA to investigate the expression profiles of TK genes fully and objectively in 918 CESC tissues and 360 control tissues. In-house tissue microarrays for immunohistochemical testing were used to verify the protein level of TK1 in 62 CESC tissues and control tissues. The growth effect of TK1 and TK2 in CESC cell lines was assessed using Chronos dependency scores derived from CRISPR knockout screen in the Achilles project. We also analyzed the potential mechanism of TK genes by studying the relationship between TK gene expression and immune infiltration, gene alternations as well as the related signal pathways.
Results:
The various detection methods employed all confirmed that the TK1 expression is upregulated and TK2 is downregulated in CESC tissues (SMD: 2.44, 95% confidence interval (CI): 1.36 - 3.51, area under curve (AUC): 0.88, 95% CI: 0.85 - 0.90; SMD: -0.69, 95% CI: -1.25 to -0.14, AUC: 0.75, 95% CI: 0.71 - 0.78). Inhibition of TK1 expression by CRISPR knockout had negative influence on the biological functions of 11 CESC cell lines. The expression of TK2 was negatively correlated with the malignant progression of CESC. Expression of TK genes showed significant association with the immune infiltration of macrophages, CD4+ T cells, and neutrophils. Genes related with TK1 or TK2 were involved in pathways related to DNA replication, proteasome, and homologous recombination.
Conclusions:
Clinically, these findings suggest that the differential expression of TK1 and TK2 could serve as potential biomarkers, as well as therapeutic targets for personalized treatment strategies in CESC patients.
Insights
Thymidine kinase 1 (TK1) is upregulated and TK2 is downregulated in cervical squamous cell carcinoma (CESC). Differential TK gene expression impacts cancer progression and immune infiltration, suggesting potential therapeutic targets.
Area of Science:
- Molecular oncology and cancer biomarkers.
- DNA synthesis and repair mechanisms in cancer.
Background:
- Thymidine kinases (TKs) are crucial for DNA synthesis and repair, with altered expression linked to various cancers.
- The roles of Thymidine kinase 1 (TK1) and Thymidine kinase 2 (TK2) in cervical squamous cell carcinoma (CESC) remain largely uncharacterized.
- Investigating TK1 and TK2 is essential for understanding CESC pathogenesis and identifying novel therapeutic strategies.
Purpose of the Study:
- To investigate the differential expression of TK1 and TK2 in CESC.
- To explore the clinical significance and molecular mechanisms of TK1 and TK2 in CESC.
- To evaluate TK1 and TK2 as potential biomarkers and therapeutic targets for CESC.
Main Methods:
- Analysis of global high-throughput data for TK1 and TK2 mRNA expression in 918 CESC and 360 control tissues.
- Immunohistochemical validation of TK1 protein levels in 62 CESC and control tissues.
- Assessment of TK1 and TK2 growth effects using CRISPR knockout data and analysis of associations with immune infiltration and signaling pathways.
Main Results:
- TK1 expression was significantly upregulated (SMD: 2.44, AUC: 0.88) and TK2 was downregulated (SMD: -0.69, AUC: 0.75) in CESC tissues.
- TK1 inhibition negatively impacted CESC cell line functions, while TK2 expression correlated negatively with malignant progression.
- TK gene expression was associated with immune cell infiltration (macrophages, CD4+ T cells, neutrophils) and pathways like DNA replication and homologous recombination.
Conclusions:
- Differential expression of TK1 and TK2 is a significant finding in CESC.
- TK1 and TK2 represent potential diagnostic biomarkers and therapeutic targets for personalized CESC treatment.
- Further research into TK-related pathways could unveil novel therapeutic strategies for CESC.
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