Construction of a Cancer Stem Cell related Histone Acetylation Regulatory Genes Prognostic Model for Hepatocellular Carcinoma via Bioinformatics Analysis: Implications for Tumor Chemotherapy and Immunity.

Qian Dai, Jie Zhu, Jing Yang, Chun-Yan Zhang, Wen-Jing Yang, Bai-Shen Pan, Xin-Rong Yang, Wei Guo, Bei-Li Wang
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Abstract

Background: Cancer stem cells (CSC) play an important role in the development of Liver Hepatocellular Carcinoma (LIHC). However, the regulatory mechanisms between acetylation- associated genes (HAGs) and liver cancer stem cells remain unclear.

Objective: To identify a set of histone acetylation genes (HAGs) with close associations to liver cancer stem cells (LCSCs), and to construct a prognostic model that facilitates more accurate prognosis assessments for LIHC patients.

Methods: LIHC expression data were downloaded from the public databases. Using mRNA expression- based stemness indices (mRNAsi) inferred by One-Class Logistic Regression (OCLR), Differentially Expressed Genes (DEGs) (mRNAsi-High VS. mRNAsi-Low groups) were intersected with DEGs (LIHC VS. normal samples), as well as histone acetylation-associated genes (HAGs), to obtain mRNAsi-HAGs. A risk model was constructed employing the prognostic genes, which were acquired through univariate Cox and Least Shrinkage and Selection Operator (LASSO) regression analyses. Subsequently, independent prognostic factors were identified via univariate and multivariate Cox regression analyses and then a nomogram for prediction of LIHC survival was developed. Additionally, immune infiltration and drug sensitivity analysis were performed to explore the relationships between prognostic genes and immune cells. Finally, the expressions of selected mRNAsi-HAGs were validated in the LIHC tumor sphere by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) assay and western blot analysis.

Results: Among 13 identified mRNAsi-HAGs, 3 prognostic genes (HDAC1, HDAC11, and HAT1) were selected to construct a risk model (mRNAsi-HAGs risk score = 0.02 * HDAC1 + 0.09 * HAT1 + 0.05 * HDAC11). T-stage, mRNAsi, and mRNAsi-HAGs risk scores were identified as independent prognostic factors to construct the nomogram, which was proved to predict the survival probability of LIHC patients effectively. We subsequently observed strongly positive correlations between mRNAsi-HAGs risk score and tumor-infiltrating T cells, B cells and macrophages/monocytes. Moreover, we found 8 drugs (Mitomycin C, IPA 3, FTI 277, Bleomycin, Tipifarnib, GSK 650394, AICAR and EHT 1864) had significant correlations with mRNAsi-HAGs risk scores. The expression of HDAC1 and HDAC11 was higher in CSC-like cells in the tumor sphere.

Conclusion: This study constructed a mRNAsi and HAGs-related prognostic model, which has implications for potential immunotherapy and drug treatment of LIHC.

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通过生物信息学分析构建与癌症干细胞相关的肝细胞癌组蛋白乙酰化调控基因预后模型:肿瘤化疗和免疫的意义
背景:癌症干细胞(CSC)在肝细胞癌(LIHC)的发展过程中发挥着重要作用。然而,乙酰化相关基因(HAGs)与肝癌干细胞之间的调控机制仍不清楚:鉴定一组与肝癌干细胞(LCSCs)密切相关的组蛋白乙酰化基因(HAGs),并构建一个预后模型,以便对LIHC患者进行更准确的预后评估:方法:从公共数据库下载LIHC表达数据。利用单类逻辑回归(OCLR)推断出的基于mRNA表达的干性指数(mRNAsi),将差异表达基因(DEGs)(mRNAsi-高组与mRNAsi-低组)与DEGs(LIHC与正常样本)以及组蛋白乙酰化相关基因(HAGs)相交,得到mRNAsi-HAGs。通过单变量 Cox 和最小收缩和选择操作器(LASSO)回归分析获得的预后基因被用于构建风险模型。随后,通过单变量和多变量 Cox 回归分析确定了独立的预后因素,并绘制了用于预测 LIHC 存活率的提名图。此外,还进行了免疫浸润和药物敏感性分析,以探讨预后基因与免疫细胞之间的关系。最后,通过定量逆转录聚合酶链反应(qRT-PCR)检测和免疫印迹分析验证了所选mRNAsi-HAGs在LIHC肿瘤球中的表达:结果:在13个已鉴定的mRNAsi-HAGs中,选择了3个预后基因(HDAC1、HDAC11和HAT1)构建风险模型(mRNAsi-HAGs风险评分=0.02 * HDAC1 + 0.09 * HAT1 + 0.05 * HDAC11)。T分期、mRNAsi和mRNAsi-HAGs风险评分被确定为独立的预后因素,从而构建了提名图,该提名图被证明能有效预测LIHC患者的生存概率。我们随后观察到,mRNAsi-HAGs 风险评分与肿瘤浸润 T 细胞、B 细胞和巨噬细胞/单核细胞之间呈强正相关。此外,我们还发现 8 种药物(丝裂霉素 C、IPA 3、FTI 277、博莱霉素、Tipifarnib、GSK 650394、AICAR 和 EHT 1864)与 mRNAsi-HAGs 风险评分有显著相关性。在肿瘤球内的CSC样细胞中,HDAC1和HDAC11的表达量较高:本研究构建了一个与mRNAsi和HAGs相关的预后模型,这对LIHC潜在的免疫疗法和药物治疗具有重要意义。
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