脊索瘤中T异构体在肿瘤复发和细胞周期中的不同作用及潜在机制的鉴定
Identification of the Different Roles and Potential Mechanisms of T Isoforms in the Tumor Recurrence and Cell Cycle of Chordomas.
作者信息
Ma Junpeng, Chen Wei, Wang Ke, Tian Kaibing, Li Qi, Zhao Tianna, Zhang Liwei, Wang Liang, Wu Zhen, Zhang Junting
机构信息
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
出版信息
Onco Targets Ther. 2019 Dec 31;12:11777-11791. doi: 10.2147/OTT.S232526. eCollection 2019.
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.
目的
T（短尾）异构体在脊索瘤中的作用尚不清楚。本研究旨在探讨它们在脊索瘤中的不同作用及机制。
患者与方法
评估57例脊索瘤中T异构体mRNA的表达，并进行预后分析。在特异性敲低T异构体mRNA后进行细胞凋亡、增殖及细胞周期检测。进行全转录组测序、基因集富集分析、基因本体分析、京都基因与基因组百科全书分析及竞争性内源RNA（ceRNA）分析。
结果
本研究表明，T长异构体是与肿瘤复发相关的显著危险因素（风险比[HR]，1.09；P = 0.018），而T短异构体是保护因素（HR，0.24；P = 0.012）。敲低T长异构体后，细胞周期停滞于G0/G1期，细胞增殖受到显著抑制。生物信息学分析显示，H19、P21和GADD45B的上调；SKP2和CDK2的下调；以及P53信号通路的伴随变化共同导致G0/G1期停滞。敲低T短异构体后，细胞周期停滞于G2/M期，细胞凋亡略有增加趋势（P = 0.067）。YWHAZ的上调以及E2F1及其靶基因的下调可能导致细胞周期停滞于G2/M期并引发凋亡。此外，建立了由长链非编码RNA、mRNA和微小RNA组成的ceRNA网络。
结论
T长异构体是脊索瘤复发的危险因素，T短异构体是保护因素。此外，细胞周期是敲低T异构体的主要靶点，下游转录组的变化可能导致特定T异构体敲低对脊索瘤细胞周期分布、凋亡及增殖变化产生不同影响。
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