Targeted Regulation of Osteoblasts and Osteoclasts in Osteosarcoma Patients by CSF3R Receptor Inhibition of Osteolysis Caused by Tumor Inflammation Based on Transcriptional Spectrum Analysis and Drug Library Screening.

Wei Duan, Yu Chen, Jinlu Shan, Qian Li
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Abstract

Background: Osteosarcoma (OS) is a common primary malignant bone tumor that mainly occurs in children and adolescents. The use of IL-8 inhibitor compounds has been reported in patents, which can be used to treat and/or prevent osteosarcoma, but the pathogenesis of osteosarcoma remains to be investigated. At present, osteoblasts and osteoclasts play an important role in the occurrence and development of OS. However, the relationship between osteoblasts and osteoclasts in the specific participation mechanism and inflammatory response of OS patients has not been further studied.

Methods: The transcriptome, clinical data, and other data related to OS were downloaded from the GEO database to analyze them with 200 known inflammatory response genes. We set the screening conditions as p < 0.05 and | log2FC| > 0.50, screened the differentially expressed genes (DEGs) related to OS, tested the correlation coefficient between the OS INF gene and clinical risk, and analyzed the survival prognosis. We further enriched and analyzed the DEGs and inflammatory response genes of OS with GO/KEGG to explore the potential biological function and signal pathway mechanism of OS inflammatory response genes. Moreover, the virtual screening of drug sensitivity of OS based on the FDA drug library was also carried out to explore potential therapeutic drugs targeted to regulate OS osteogenesis and osteoclast inflammation, and finally, the molecular dynamics simulation verification of OS core protein and potential drugs was carried out to explore the binding stability and mechanism between potential drugs and core protein.

Results: Through differential analysis of GSE39058, GSE36001, GSE87624, and three other data sets closely related to OS osteoblasts and osteoclasts, we found that there was one upregulated gene (CADM1) and one down-regulated gene (PHF15) related to OS. In addition, GSEA enrichment analysis of the DEGs of OS showed that it was mainly involved in the progress of OS through biological functions, such as oxidative photosynthesis, acute junction, and epithelial-mesenchymal transition. The enrichment analysis of OS DEGs revealed that they mainly affect the occurrence and progress of OS by participating in the regulation of the actin skeleton, PI3K Akt signal pathway, complement and coagulation cascade. According to the expression of CSF3R in OS patients, a risk coefficient model and a diagnostic model were established. It was found that the more significant the difference in the CSF3R gene in OS patients, the greater the risk coefficient of disease (p < 0.05). The AUC under the curve of the CSF3R gene was greater than 0.65, which had a good diagnostic significance for OS. The above results showed that the prognosis risk gene CSF3R related to OS inflammation was closely related to the survival status of OS patients. Finally, through the virtual screening of the ZINC drug library and molecular dynamics simulation, it was found that the docking model formed by the core protein CSF3R and the compounds, Leucovorin and Methotrexate, were the most stable, which revealed that the compounds Leucovorin and Methotrexate might play a role in the treatment of OS by combining with the inflammatory response related factor CSF3R of OS.

Conclusion: CSF3R participates in the occurrence and development of OS bone destruction by regulating the inflammatory response of osteoblasts and osteoclasts and can affect the survival prognosis of OS patients.

基于转录谱分析和药物文库筛选的CSF3R受体抑制肿瘤炎症引起的骨溶解对骨肉瘤患者成骨细胞和破骨细胞的靶向调节
背景:骨肉瘤是一种常见的原发性恶性骨肿瘤,主要发生在儿童和青少年。IL-8抑制剂化合物的使用已在专利中报道,其可用于治疗和/或预防骨肉瘤,但骨肉瘤的发病机制仍有待研究。目前,成骨细胞和破骨细胞在OS的发生和发展中起着重要作用。然而,成骨细胞和破骨细胞在OS患者特定参与机制和炎症反应中的关系尚未得到进一步研究。方法:从GEO数据库下载转录组、临床数据和其他与OS相关的数据,用200个已知的炎症反应基因对其进行分析。我们将筛选条件设置为p<0.05和|log2FC|>0.50,筛选与OS相关的差异表达基因(DEGs),检测OS INF基因与临床风险的相关系数,并分析生存预后。我们用GO/KEGG进一步丰富和分析了OS的DEG和炎症反应基因,以探索OS炎症反应基因的潜在生物学功能和信号通路机制。此外,还基于美国食品药品监督管理局药物库对OS的药物敏感性进行了虚拟筛选,以探索潜在的治疗药物,靶向调节OS成骨和破骨细胞炎症,最后,对OS核心蛋白和潜在药物进行了分子动力学模拟验证,以探索潜在药物与核心蛋白结合的稳定性和机制。结果:通过对GSE39058、GSE36001、GSE87624和其他三个与OS成骨细胞和破骨细胞密切相关的数据集的差异分析,我们发现有一个上调基因(CADM1)和一个下调基因(PHF15)与OS相关。此外,GSEA对OS DEG的富集分析表明,它主要通过氧化光合作用、急性连接和上皮-间质转化等生物学功能参与OS的进展。OS DEGs的富集分析表明,它们主要通过参与肌动蛋白骨架、PI3K-Akt信号通路、补体和凝血级联的调节来影响OS的发生和进展。根据CSF3R在OS患者中的表达,建立了危险系数模型和诊断模型。研究发现,OS患者的CSF3R基因差异越显著,疾病的危险系数越大(p结论:CSF3R通过调节成骨细胞和破骨细胞的炎症反应参与OS骨破坏的发生和发展,并可影响OS患者的生存预后。
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