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mA 相关血管生成基因构建预后标志物,揭示肝癌免疫和氧化应激全景,并筛选药物。

mA-Related Angiogenic Genes to Construct Prognostic Signature, Reveal Immune and Oxidative Stress Landscape, and Screen Drugs in Hepatocellular Carcinoma.

机构信息

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.

School of Basic Medicine, Fourth Military Medical University, 169 Changle West Rd, Xi'an 710032, China.

出版信息

Oxid Med Cell Longev. 2022 Sep 30;2022:8301888. doi: 10.1155/2022/8301888. eCollection 2022.

Abstract

BACKGROUND

mA modification plays a key role in the development of hepatocellular carcinoma (HCC). Angiogenesis-related genes (ARGs) are increasingly being used to define signatures predicting patient prognosis. The correlations between mA-related ARGs (mARGs), clinical outcomes, and the immune and oxidative stress landscape are unclear.

METHODS

Univariate Cox regression analysis of 24 mARGs yielded 13 prognostic genes, which were then analyzed for their enriched functions and pathways. After LASSO regression analysis, a prognostic signature was constructed and its reliability validated. Patients were grouped by risk using the signature score, and then the clinical prognosis, the immune landscape, and the oxidative stress landscape between the two groups were analyzed. Drug sensitivity analysis was performed to identify potentially efficient therapeutic agents.

RESULTS

Thirteen prognosis-related mARGs consistently clustered patients with HCC into four groups with significantly different prognosis. Four mARGs (, , , and ) were used to construct a prognostic signature and define risk groups. Among them, , , and , were defined as prognostic risk factors, while was defined as a prognostic protective factor. Compared to low-risk patients, HCC patients in the high-risk group had a poorer prognosis and showed significant differences in clinical characteristics, enriched pathways, tumor stemness, and tumor microenvironment. The drug sensitivity of oxaliplatin and LDK-378 negatively correlated with ITGAV expression. Ten drugs had lower IC50s in the high-risk group, indicating better antitumor efficacy than in the low-risk group, with epothilone B having the lowest IC50 value.

CONCLUSIONS

A prognostic model consisting of mARGs can be used to predict the prognosis of HCC patients. The risk grouping of our model can be used to reveal differences in the tumor immune microenvironment of patients with HCC. Further in-depth study may provide new targets for future treatment.

摘要

背景

mA 修饰在肝细胞癌(HCC)的发展中起着关键作用。越来越多的血管生成相关基因(ARGs)被用于定义预测患者预后的特征。mA 相关 ARGs(mARGs)与临床结局以及免疫和氧化应激景观之间的相关性尚不清楚。

方法

对 24 个 mARGs 进行单因素 Cox 回归分析,得到 13 个预后基因,然后对其进行富集功能和通路分析。经过 LASSO 回归分析,构建了预后标志并验证其可靠性。根据signature 评分将患者分为不同的风险组,然后分析两组之间的临床预后、免疫景观和氧化应激景观。进行药物敏感性分析以确定潜在有效的治疗药物。

结果

13 个预后相关的 mARGs 一致地将 HCC 患者聚类为四个具有显著不同预后的组。四个 mARGs(ITGAV、MMP9、SERPINE1 和 THBS1)被用于构建预后标志并定义风险组。其中,ITGAV、MMP9、SERPINE1 和 THBS1 被定义为预后危险因素,而 VEGFA 被定义为预后保护因素。与低风险患者相比,高风险组的 HCC 患者预后较差,且在临床特征、富集通路、肿瘤干性和肿瘤微环境方面存在显著差异。奥沙利铂和 LDK-378 的药物敏感性与 ITGAV 表达呈负相关。在高风险组中,有 10 种药物的 IC50 较低,表明其抗肿瘤疗效优于低风险组,其中表柔比星的 IC50 值最低。

结论

由 mARGs 组成的预后模型可用于预测 HCC 患者的预后。我们模型的风险分组可用于揭示 HCC 患者肿瘤免疫微环境的差异。进一步的深入研究可能为未来的治疗提供新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4be/9554665/8811d455e2f9/OMCL2022-8301888.001.jpg

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