Zhang Zhao, Liu Xincheng, Cheng Debin, Dang Jingyi, Mi Zhenzhou, Shi Yubo, Wang Lei, Fan Hongbin
Division of Musculoskeletal Cancer Service, Department of Orthopaedic Surgery, Xi-jing Hospital, The Fourth Military Medical University, Xi'an, China.
Front Genet. 2022 Jun 8;13:911346. doi: 10.3389/fgene.2022.911346. eCollection 2022.
Osteosarcoma is a highly malignant bone tumor commonly occurring in adolescents with a poor 5-year survival rate. The unfolded protein response (UPR) can alleviate the accumulation of misfolded proteins to maintain homeostasis under endoplasmic reticulum stress. The UPR is linked to the occurrence, progression, and drug resistance of tumors. However, the function of UPR-related genes (UPRRGs) in disease progression and prognosis of osteosarcoma remains unclear. The mRNA expression profiling and corresponding clinical features of osteosarcoma were acquired from TARGET and GEO databases. Consensus clustering was conducted to confirm different UPRRG subtypes. Subsequently, we evaluated the prognosis and immune status of the different subtypes. Functional analysis of GO, GSEA, and GSVA was used to reveal the molecular mechanism between the subtypes. Finally, four genes (, , , and ) were screened to construct and validate a risk signature to predict the prognosis of patients with osteosarcoma. We identified two subtypes according to the UPRRG expression patterns. The subgroup with higher immune scores, lower tumor purity, and active immune status was linked to a better prognosis. Meanwhile, functional enrichment revealed that immune-related signaling pathways varied markedly in the two subtypes, suggesting that the UPR might influence the prognosis of osteosarcoma influencing the immune microenvironment. Moreover, prognostic signature and nomogram models were developed based on UPRRGs, and the results showed that our model has an excellent performance in predicting the prognosis of osteosarcoma. qPCR analysis was also conducted to verify the expression levels of the four genes. We revealed the crucial contribution of UPRRGs in the immune microenvironment and prognostic prediction of osteosarcoma patients and provided new insights for targeted therapy and prognostic assessment of the disease.
骨肉瘤是一种高度恶性的骨肿瘤，常见于青少年，5年生存率较低。未折叠蛋白反应（UPR）可以缓解错误折叠蛋白的积累，以在内质网应激下维持体内稳态。UPR与肿瘤的发生、发展和耐药性有关。然而，UPR相关基因（UPRRGs）在骨肉瘤疾病进展和预后中的作用仍不清楚。从TARGET和GEO数据库中获取骨肉瘤的mRNA表达谱及相应的临床特征。进行一致性聚类以确认不同的UPRRG亚型。随后，我们评估了不同亚型的预后和免疫状态。使用GO、GSEA和GSVA的功能分析来揭示亚型之间的分子机制。最后，筛选出四个基因（、、、和）构建并验证风险特征，以预测骨肉瘤患者的预后。我们根据UPRRG表达模式确定了两种亚型。免疫评分较高、肿瘤纯度较低且免疫状态活跃的亚组与较好的预后相关。同时，功能富集显示免疫相关信号通路在两种亚型中差异显著，表明UPR可能通过影响免疫微环境来影响骨肉瘤的预后。此外，基于UPRRGs建立了预后特征和列线图模型，结果表明我们的模型在预测骨肉瘤预后方面具有优异的性能。还进行了qPCR分析以验证这四个基因的表达水平。我们揭示了UPRRGs在骨肉瘤患者免疫微环境和预后预测中的关键作用，并为该疾病的靶向治疗和预后评估提供了新的见解。
