PDF(Pubmed)
Abstract：
Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.
摘要：
骨肉瘤,儿童和青少年中最常见的原发性恶性肿瘤之一，主要特点是预后差、转移率高。本研究使用来自两种不同细胞系的超增强子相关基因，为骨肉瘤患者构建了五种新型的超增强子相关基因预后模型。训练和测试数据集用于确认五个超增强子相关基因的预后模型，这导致了骨肉瘤的公正预测因素。免疫治疗和对抗癌药物反应的预测表明，五个超增强子相关基因的风险特征与化学敏感性呈正相关。此外，对风险特征基因的功能分析揭示了基因群与肿瘤恶性特征之间的显著关系.选择TNF受体超家族成员11b(TNFRSF11B)用于功能验证。沉默TNFRSF11B抑制增殖，迁移,和骨肉瘤细胞的体外侵袭和体内抑制骨肉瘤的生长。此外，对MG-63细胞进行转录组测序，研究TNFRSF11B在骨肉瘤细胞中的调控机制，发现TNFRSF11B通过磷酸肌醇3-激酶信号通路参与骨肉瘤的发展。在鉴定TNFRSF11B为关键基因后，我们选择了特异性靶向该基因的抑制剂,并进行了分子对接模拟.此外,利塞膦酸在细胞和分子水平上都抑制骨肉瘤的生长。总之,超增强子相关基因标签是骨肉瘤预后和治疗的可行治疗工具.
