Liu Weihai, Regmi Moksada, Liu Shikun, Xiong Ying, Dai Yuwei, Wang Yingjie, Yang Jun, Yang Chenlong
State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Neurosurgery, Peking University Third Hospital, Peking University, No. 49, Garden North Road, Haidian District, Beijing, 100191, People's Republic of China.
Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, People's Republic of China.
Sci Rep. 2025 Jun 6;15(1):19942. doi: 10.1038/s41598-025-04508-0.
Chordomas are rare, aggressive tumors of the axial skeleton with limited treatment options. Genetic alterations in SMARCB1, a tumor suppressor gene, have been implicated in poorly differentiated chordomas, but their role in typical and chondroid subtypes remains unclear. This study examined 42 chordoma samples (26 typical, 16 chondroid) for SMARCB1 genetic alterations, expression patterns, and associated pathways. SMARCB1 knockdown experiments were conducted in chordoma cell lines, followed by comprehensive transcriptome analysis. No exonic SMARCB1 mutations were identified, but heterozygous loss was observed in 3/26 typical chordomas. SMARCB1 expression positively correlated with patient survival and epithelial-mesenchymal markers. Functional studies revealed that SMARCB1 knockdown significantly enhanced cell proliferation, migration, and invasion. Transcriptome analysis demonstrated enrichment of MYC targets, E2F targets, and cell cycle pathways in SMARCB1-low samples, while cellular adhesion pathways were downregulated. Notably, SLPI, LBH, and LOXL2 were significantly downregulated in SMARCB1-low samples. SMARCB1 plays an important role in chordoma progression, influencing prognosis and cellular behavior, despite infrequent genetic alterations. Its effects on key oncogenic pathways and cellular plasticity suggest potential for targeted therapies. These findings provide new insights into chordoma biology and lay the groundwork for developing SMARCB1-based prognostic tools and personalized treatment strategies.
脊索瘤是一种罕见的、侵袭性的中轴骨肿瘤，治疗选择有限。肿瘤抑制基因SMARCB1的基因改变与低分化脊索瘤有关，但其在典型和软骨样亚型中的作用仍不清楚。本研究检测了42例脊索瘤样本（26例典型，16例软骨样）的SMARCB1基因改变、表达模式及相关通路。在脊索瘤细胞系中进行了SMARCB1敲低实验，随后进行全面的转录组分析。未发现外显子SMARCB1突变，但在3/26例典型脊索瘤中观察到杂合性缺失。SMARCB1表达与患者生存率及上皮-间质标志物呈正相关。功能研究表明，SMARCB1敲低显著增强细胞增殖、迁移和侵袭。转录组分析显示，在SMARCB1低表达样本中MYC靶点、E2F靶点和细胞周期通路富集，而细胞黏附通路下调。值得注意的是，SLPI、LBH和LOXL2在SMARCB1低表达样本中显著下调。尽管基因改变不常见，但SMARCB1在脊索瘤进展中起重要作用，影响预后和细胞行为。其对关键致癌通路和细胞可塑性的影响提示了靶向治疗的潜力。这些发现为脊索瘤生物学提供了新见解，为开发基于SMARCB1的预后工具和个性化治疗策略奠定了基础。
