TY - JOUR
T1 - Identification of the different roles and potential mechanisms of t isoforms in the tumor recurrence and cell cycle of chordomas
AU - Ma, Junpeng
AU - Chen, Wei
AU - Wang, Ke
AU - Tian, Kaibing
AU - Li, Qi
AU - Zhao, Tianna
AU - Zhang, Liwei
AU - Wang, Liang
AU - Wu, Zhen
AU - Zhang, Junting
N1 - Funding Information:
This study was funded by the National Natural Science Foundation of China (81472370, Dr. Junting Zhang; 81672506, Dr. Zhen Wu; 81802683, Dr. Kaibing Tian).
Funding Information:
1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People’s Republic of China; 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 4Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, People’s Republic of China; 6Beijing Key Laboratory of Brian Tumor, Beijing, People’s Republic of China Correspondence: Junting Zhang; Liang Wang Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of China Tel +86-10-59978431 Fax +86-10-59971377 Email [email protected]; [email protected]
Publisher Copyright:
© 2019 Ma et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Brachyury
KW - CeRNA
KW - Cell cycle
KW - Chordoma
KW - Prognosis
KW - Whole-transcriptome sequencing
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U2 - 10.2147/OTT.S232526
DO - 10.2147/OTT.S232526
M3 - Article
AN - SCOPUS:85078557763
SN - 1178-6930
VL - 12
SP - 11777
EP - 11791
JO - OncoTargets and Therapy
JF - OncoTargets and Therapy
ER -