OncoTargets and Therapy (Jan 2020)
Identification of the Different Roles and Potential Mechanisms of T Isoforms in the Tumor Recurrence and Cell Cycle of Chordomas
Abstract
Junpeng Ma,1 Wei Chen,2 Ke Wang,1 Kaibing Tian,1 Qi Li,3 Tianna Zhao,4 Liwei Zhang,1,3,5,6 Liang Wang,1,5,6 Zhen Wu,1,3,5,6 Junting Zhang1,5,6 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 ChinaCorrespondence: Junting Zhang; Liang WangBeijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel +86-10-59978431Fax +86-10-59971377Email [email protected]; [email protected]: 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
