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Identification of the Different Roles and Potential Mechanisms of T Isoforms in the Tumor Recurrence and Cell Cycle
Junpeng Ma1, Wei Chen2, Ke Wang1
1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
Purpose:
The roles of T (brachyury) isoforms in chordomas remain unclear. This study aimed to investigate the different roles and mechanisms of them in chordomas.
Patients And Methods:
The expression of T isoforms mRNAs in 57 chordomas was assessed, and a prognosis analysis was conducted. Cell apoptosis, proliferation and cell cycle assays were performed after specific T isoform mRNA knockdown. Whole-transcriptome sequencing, Gene Set Enrichment Analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis and competing endogenous RNA (ceRNA) analysis were conducted.
Results:
As revealed in this study, the T-long isoform was a significant risk factor (hazard ratio [HR], 1.09; P=0.018) and the T-short isoform was a protective factor (HR, 0.24; P=0.012) associated with tumor recurrence. After T-long isoform knockdown, the cell cycle was arrested at G0/G1 phase and cell proliferation was significantly inhibited. A bioinformatic analysis revealed that the upregulation of H19, P21 and GADD45B; downregulation of SKP2 and CDK2; and accompanying changes in the P53 signaling pathway consistently contributed to G0/G1 arrest. After T-short isoform knockdown, the cell cycle was arrested at G2/M phase and cell apoptosis tended to increase slightly (P=0.067). The upregulation of YWHAZ and downregulation of E2F1 and its target genes might contribute to cell cycle arrest in G2/M phase and apoptosis. In addition, the ceRNA network, consisting of long noncoding RNAs, mRNAs and microRNAs, was established.
Conclusion:
The T-long isoform was a risk factor and the T-short isoform was a protective factor for chordoma recurrence. In addition, the cell cycle was the main target of T isoforms knockdown, and the changes in the downstream transcriptome may contribute to the different effects of specific T isoform knockdown on the changes in the cell cycle distributions and apoptosis and proliferation of chordoma cells.
Insights
The T-long isoform promotes chordoma recurrence, while the T-short isoform protects against it. Targeting cell cycle pathways with T isoforms influences tumor growth and apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chordomas are rare bone tumors with unclear molecular drivers.
- T (brachyury) isoforms are implicated in development but their specific roles in chordomas are unknown.
Purpose of the Study:
- To investigate the distinct roles and underlying mechanisms of T-long and T-short isoforms in chordoma.
- To identify T isoforms as potential prognostic markers and therapeutic targets.
Main Methods:
- Assessed T isoform mRNA expression in 57 chordomas and performed prognostic analysis.
- Utilized cell apoptosis, proliferation, and cell cycle assays post-T isoform knockdown.
- Conducted whole-transcriptome sequencing and bioinformatic analyses (GSEA, GO, KEGG, ceRNA).
Main Results:
- T-long isoform correlated with increased tumor recurrence risk (HR=1.09), while T-short isoform showed a protective effect (HR=0.24).
- T-long knockdown induced G0/G1 cell cycle arrest and inhibited proliferation, involving P53 signaling pathway alterations.
- T-short knockdown caused G2/M cell cycle arrest and a trend towards increased apoptosis, potentially via YWHAZ/E2F1 pathways.
Conclusions:
- T-long and T-short isoforms exhibit opposing roles in chordoma recurrence.
- Cell cycle regulation is a key mechanism affected by T isoforms.
- Downstream transcriptomic changes mediate the differential effects of T isoforms on chordoma cell behavior.
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