RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
解析鞘脂代谢基因在骨肉瘤进展和微环境中的作用以构建预后特征
英文原题：Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature.
查看英文原题
Dissecting the effect of sphingolipid metabolism gene in progression and microenvironment of osteosarcoma to develop a prognostic signature.
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中文摘要
鞘脂代谢（SM）促进骨肉瘤（OS）的肿瘤发生和恶性进展，导致不良预后。阐明SM在骨肉瘤中的分子机制并开发基于SM的预后特征在临床环境中可能有益。
本研究纳入88例冷冻OS样本，利用单因素Cox回归识别OS发展中的关键SM相关基因。对SM相关基因进行最小绝对收缩和选择算子（LASSO）回归分析，以最小化过拟合风险。利用多因素Cox回归分析生成预后特征，并在验证队列中进行验证。
此外，与SM相关的细胞和分子机制对OS患者具有不良预后，并已被广泛研究。结果，根据关键预后基因（CBS、GLB1和HACD1）建立了基于SM的预后风险模型，该模型具有出色的预测OS患者预后的能力（训练队列的AUC为0.887，验证队列的AUC为0.737）。根据该预后特征识别的高风险OS患者具有显著较差的免疫微环境，表现为免疫评分显著降低（均值=216.290 ± 662.463），25种免疫细胞浸润减少，包括NK细胞（LogFC= -0.3597）、CD8+T细胞（LogFC=-0.2346）、细胞溶解活性（LogFC=-0.1998）等。免疫抑制微环境可能是由于糖脂SM失调所致。
此外，通过整合基于SM的预后特征和临床参数构建了列线图，以促进临床应用。该列线图能够准确预测OS患者的预后。总体而言，本研究阐明了SM在OS发展中的功能，并有助于开发一种基于SM相关基因的风险分层工具，应用于临床环境。我们的研究结果将有助于识别高风险患者并提供个体化治疗。
展开英文摘要原文
Sphingolipid metabolism (SM) fuels tumorigenesis and the malignant progression of osteosarcoma (OS), which leads to an unfavorable prognosis. Elucidating the molecular mechanisms underlying SM in osteosarcoma and developing a SM-based prognostic signature could be beneficial in the clinical setting.
This study included 88 frozen OS samples to recognize the vital SM-relevant genes in the development of OS utilizing univariate Cox regression. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was conducted on the SM- relevant genes to minimize the risk of overfitting. The prognostic signature was generate utilizing the multivariable Cox regression analysis and was verified in the validation cohort.
Moreover, cellular and molecular mechanisms associated with SM have an unfavorable prognosis for OS patients and have been widely studied. Resultantly, an SM-based prognostic risk model was established according to critical prognostic genes (CBS , GLB1 , and HACD1) , which had an excellent ability to predict the prognosis of OS patients (AUC for the train cohort was 0. 887 and AUC for validation cohort was 0. 737).
The high-risk OS patients identified based on this prognostic signature had significantly poor immune microenvironment, indicated by significantly low immune score (mean=216. 290 ± 662. 463), reduced infiltrations of 25 immune cells, including NK cells (LogFC= -0. 3597), CD8+T cells ((LogFC=-0. 2346), Cytolytic activity ((LogFC=-0. 1998), etc. The immunosuppressive microenvironment could be due to dysregulated SM of glycolipids.
Further, a nomogram was constructed by integrating the SM-based prognostic signature and clinical paraments to facilitate clinical application. The nomogram could accurately predict the prognosis of OS invalids. Collectively, this study clarified the function of SM in the development of OS and helped develop a tool for risk stratification based on SM-related genes with application in clinical settings. The results of our study will aid in identifying high-risk patients and provide individualized treatments.
论文信息
- 作者
- Zhong Y、Zhang Y、Wei S、Chen J、Zhong C、Cai W、Jin W、Peng H
- 单位
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Frontiers in endocrinology2022
- 原文标识
- PubMed 36313783 · DOI 10.3389/fendo.2022.1030655
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