Identification of the Different Roles and Potential Mechanisms of T Isoforms in the Tumor Recurrence and Cell Cycle of Chordomas

Junpeng Ma; Wei Chen; Ke Wang; Kaibing Tian; Qi Li; Tianna Zhao; Liwei Zhang; Liang Wang; Zhen Wu; Junting Zhang

doi:10.2147/OTT.S232526

Identification of the Different Roles and Potential Mechanisms of T Isoforms in the Tumor Recurrence and Cell Cycle of Chordomas

Onco Targets Ther. 2019 Dec 31:12:11777-11791. doi: 10.2147/OTT.S232526. eCollection 2019.

Authors

Junpeng Ma¹, Wei Chen², Ke Wang¹, Kaibing Tian¹, Qi Li³, Tianna Zhao⁴, Liwei Zhang^{1

3

5

6}, Liang Wang^{1

5

6}, Zhen Wu^{1

3

5

6}, Junting Zhang^{1

5

6}

Affiliations

¹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
² Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
³ China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China.
⁴ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, People's Republic of China.
⁶ Beijing Key Laboratory of Brian Tumor, Beijing, People's Republic of China.

Abstract

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.

Keywords: brachyury; ceRNA; cell cycle; chordoma; prognosis; whole-transcriptome sequencing.