用于腔内乳腺癌免疫景观分析和预后风险预测的乙酰化相关基因标记的构建和验证

IF 6 2区 医学 Q1 ONCOLOGY
Mengdi Zhu, Jinna Lin, Haohan Liu, Jingru Wang, Nianqiu Liu, Yudong Li, Hongna Lai, Qianfeng Shi
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引用次数: 0

摘要

背景:表观遗传乙酰化在腔内乳腺癌的发生和耐药过程中起重要作用。然而,腔内乳腺癌的乙酰化调控网络仍未得到充分研究。方法:利用TCGA-BRCA数据库,探索腔内乳腺癌的乙酰化调控网络。使用Spearman相关系数、Cox比例风险和STRING数据库来识别腔内乳腺癌中与乙酰化调节分子相关的基因,并可以预测患者预后。通过Consensus Cluster Plus和LASSO风险模型构建乙酰化监管风险模型。采用GSEA、K-M生存分析、受试者工作特征(ROC)曲线分析风险模型的生存及可能的调控途径。使用TIDE、Microenvironment Cell Populations-counter和CIBERSORT算法分析风险模型人群的免疫景观。采用患者肿瘤标本检测KAT2B和TAF1L的表达。采用细胞活力、Transwell、western blotting、RT-qPCR等实验验证乳腺癌细胞系MCF-7和T47D的风险模型。建立小鼠模型,在体内验证KAT2B和TAF1L的功能。结果:在我们的研究中,我们利用TCGA-BRCA数据库对腔内乳腺癌的乙酰化调控模式进行了全面的分析。采用Consensus Cluster Plus和LASSO风险模型,筛选6个乙酰化相关基因(KAT2B、TAF1L、CDC37、CCDC107、C17orf106、ASPSCR1),构建6基因腔内乳腺癌风险模型。基于该模型,将腔内乳腺癌患者分为高危亚组和低危亚组。高危亚组预后较差。进一步分析显示,高风险亚组与较低的CD8 + t细胞浸润和对免疫检查点抑制剂治疗的更大反应性相关。体外和体内实验表明,敲低KAT2B和TAF1L可显著抑制肿瘤细胞的增殖。体外实验还显示,敲低KAT2B和TAF1L可显著抑制肿瘤细胞迁移,增加淋巴细胞浸润,并显著上调腔内乳腺癌细胞中CD8 + t细胞相关趋化因子的表达。结论:本研究成功构建了腔内乳腺癌6基因乙酰化相关风险模型,为个体化治疗提供了新的方向和依据。我们的研究结果也提示KAT2B和TAF1L可能是腔内乳腺癌的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Construction and validation of acetylation-related gene signatures for immune landscape analysis and prognostication risk prediction in luminal breast cancer.

Background: Epigenetic acetylation plays an essential role in the development and drug resistance of luminal breast cancer. However, the acetylation regulatory network in luminal breast cancer remains underexplored.

Methods: We used the TCGA-BRCA database to explore the acetylation regulatory network in luminal breast cancer. Spearman correlation coefficients, Cox proportional hazards, and the STRING database were used to identify genes that were correlated with acetylation regulatory molecules in luminal breast cancer and could predict patient outcomes. An acetylation regulatory risk model was constructed via Consensus Cluster Plus and the LASSO risk model. GSEA, K‒M survival analysis, and receiver operating characteristic (ROC) curve analysis were used to analyze survival and possible regulatory pathways of the risk model. TIDE, Microenvironment Cell Populations-counter, and CIBERSORT algorithms were used to analyze the immune landscape of the risk model population. Patients' tumor specimens were used to detect the expression of KAT2B and TAF1L. The luminal breast cancer cell lines MCF-7 and T47D were used in cell viability, Transwell, western blotting, and RT‒qPCR experiments to confirm the risk model. Mouse model was constructed for in vivo validation of KAT2B and TAF1L function.

Results: In our study, we utilized the TCGA-BRCA database to conduct a comprehensive analysis of the acetylation regulatory pattern in luminal breast cancer. Using Consensus Cluster Plus and the LASSO risk model, we screened 6 acetylation-related genes (KAT2B, TAF1L, CDC37, CCDC107, C17orf106, and ASPSCR1) and constructed a 6-gene risk model of luminal breast cancer. Based on this model, luminal breast cancer patients were classified into high- and low-risk subgroups. The high-risk subgroup had a poor prognosis. Further analysis revealed that the high-risk subgroup was associated with lower CD8 + T-cell infiltration and greater responsiveness to immune checkpoint inhibitor therapy. In vitro and in vivo experiments revealed that knockdown of KAT2B and TAF1L dramatically inhibited tumor cell proliferation. In vitro experiments also showed knockdown of KAT2B and TAF1L dramatically inhibited tumor cell migration, increased lymphocyte infiltration, and significantly upregulated the expression of CD8 + T-cell-associated chemokines in luminal breast cancer cells.

Conclusions: In this study, we successfully constructed a 6-gene acetylation-associated risk model for luminal breast cancer, providing a new direction and evidence for personalized treatment. Our results also suggested that KAT2B and TAF1L might serve as potential therapeutic targets in luminal breast cancer.

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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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