Integrated multi-omics analyses and functional validation reveal TTK as a novel EMT activator for endometrial cancer

Abstract

Background Cancer-testis antigens (CTAs) are often expressed in tumor and testicular tissues but not in other normal tissues. To date, there has been no comprehensive study of the expression and clinical significance of CTA genes associated with endometrial cancer (EC) development. Additionally, the clinical relevance, biological role, and molecular mechanisms of the CTA gene TTK protein kinase (TTK) in EC are yet to be fully understood. Methods Using bioinformatics methods, we comprehensively investigated the genomic, transcriptomic, and epigenetic changes associated with aberrant TTK overexpression in EC samples from the TCGA database. We further investigated the mechanisms of the lower survival associated with TTK dysregulation using single-cell data of EC samples from the GEO database. Cell functional assays were used to confirm the biological roles of TTK in EC cells. Results We identified 80 CTA genes that were more abundant in EC than in normal tissues, and high expression of TTK was significantly linked with lower survival in EC patients. Furthermore, ROC analysis revealed that TTK could accurately distinguish stage I EC tissues from benign endometrial samples, suggesting that TTK has the potential to be a biomarker for early EC detection. We found TTK overexpression was more prevalent in EC patients with high-grade, advanced tumors, serous carcinoma, and TP53 alterations. Furthermore, in EC tissue, TTK expression showed a strong positive correlation with EMT-related genes. With single-cell transcriptome data, we identified a proliferative cell subpopulation with high expression of TTK and known epithelial–mesenchymal transition (EMT)-related genes and transcription factors. When proliferative cells were grouped according to TTK expression levels, the overexpressed genes in the TTKhigh group were shown to be functionally involved in the control of chemoresistance. Utilizing shRNA to repress TTK expression in EC cells resulted in substantial decreases in cell proliferation, invasion, EMT, and chemoresistance. Further research identified microRNA-21 (miR-21) as a key downstream regulator of TTK-induced EMT and chemoresistance. Finally, the TTK inhibitor AZ3146 was effective in reducing EC cell growth and invasion and enhancing the apoptosis of EC cells generated by paclitaxel. Conclusion Our findings establish the clinical significance of TTK as a new biomarker for EC and an as-yet-unknown carcinogenic function. This present study proposes that the therapeutic targeting of TTK might provide a viable approach for the treatment of EC.

Annexin A2 combined with TTK accelerates esophageal cancer progression via the Akt/mTOR signaling pathway

“…2J–L ). Furthermore, we explored whether TTK regulates the expression of ANXA2 through AZ3146, a specific inhibitor of TTK [ 32 ]. We obtained the IC50 values of the ECA109 and KYSE30 cell lines by CCK8, which were 30.27 μmol/L and 23.88 μmol/L respectively (Fig.…”

Altered threonine tyrosine kinase (TTK) expression is associated with adverse clinical outcomes in breast tumors: An in silico approach

“…A recent study carried out by Albogami, in which The Human Protein Atlas database was accessed to evaluate the protein and gene expression levels of threonine tyrosine kinase (TTK) in different samples, negative regulation of threonine tyrosine kinase (TTK) was observed at both the transcriptional and protein levels in non-cancerous tissues adjacent, but high levels were detected in tumor samples (Albogami, 2022). Additionally, other studies have also demonstrated that threonine tyrosine kinase (TTK) is highly expressed in neoplastic tissues when compared to adjacent healthy or benign tissue, such as in endometrial and bladder cancer (F. Chen et al, 2018;Miao et al, 2023). Regarding epigenetic mechanisms, we investigated whether methylation could be a gene regulation pathway for threonine tyrosine kinase (TTK).…”