基于生物信息学分析HDAC8在结肠癌中的临床意义及其与免疫浸润的关系

doi:10.3877/cma.j.issn.1674-0793.2024.04.007

目的

探讨组蛋白乙酰化修饰基因HDAC8对结肠癌患者预后的影响，及其与免疫浸润的相关性。

方法

采用单因素和多因素Cox回归、Kaplan-Meier曲线分析HDAC8与结肠癌患者预后的相关性；采用GO富集分析探索HDAC8在结肠癌中的潜在作用；采用ESTIMATE算法、CIBERSORT、ssGSEA分析HDAC8与结肠癌肿瘤免疫浸润的相关性。

结果

聚类分析将结肠癌患者分为三个亚组，其中Group3的患者预后差。Group3中高表达基因HDAC8与肿瘤免疫微环境和患者预后差相关。HDAC8在结肠癌组织中表达上调（P<0.001），主要与免疫应答、防御反应等生物学过程相关。HDAC8高表达组中ESTIMATE评分、基质评分和免疫评分较低，而肿瘤纯度较高（P<0.01）。HDAC8与树突状细胞、CD8⁺T细胞、B细胞和NK细胞等多种免疫细胞浸润呈负相关。HDAC8高表达组中树突状细胞活性、成熟评分较低，CD8⁺T细胞幼稚评分较高，而杀伤功能、耗竭功能评分较低（P<0.001）。

结论

HDAC8的表达与结肠癌患者预后密切相关，其可能通过介导树突状细胞的成熟障碍影响T细胞成熟，参与形成肿瘤组织中失能的免疫微环境，调控结肠癌的发生与发展。

关键词: 结肠肿瘤, 组蛋白乙酰化修饰, HDAC8, 生物信息学, 预后, 免疫浸润

Objective

To investigate the prognosis, expression of histone acetylation and its correlation with immune infiltration in colon cancer.

Methods

Univariate and multivariate Cox regression and Kaplan-Meier curve were utilized to evaluate the relationship between HDAC8 gene expression and prognosis of COAD patients. GO enrichment analysis was performed for the potential role of HDAC8 in colon cancer. The connection between HDAC8 and tumor infiltrating immune cells was analyzed based on ESTIMATE, CIBERSORT and ssGSEA.

Results

Cluster analysis results showed that three acetylation modification subgroups were identified. The highly expressed HDAC8 in Group3 was upregulated in colon cancer tissues and associated with poor prognosis. HDAC8 was closely associated with tumor immune microenvironment such as stromal, immune scores and tumor purity. HDAC8 expression indicated significantly negative correlations with the infiltration of cells such as dendritic cells, CD8⁺ T cells, B cells and NK cells. It was negatively correlated with the activation, maturation, cytotoxicity and costimulatory scores of dendritic cell and CD8⁺ T cells.

Conclusions

The expression of HDAC8 is closely related to the prognosis of colon cancer patients. It may affect the maturation of dendritic cells and T cells, participate in the formation of dysfunctional immune microenvironment in tumor tissues, and regulate the development of colon cancer.

Key words: Colonic neoplasms, Histone acetylation, HDAC8, Bioinformatics, Prognosis, Immune infiltration

图1 结肠癌患者中组蛋白乙酰化修饰基因的聚类分析　A为一致性累计分布函数图；B为CDF曲线下面积变化图；C为K=3时的一致性聚类热图；D为三个聚类亚组的结肠癌患者组蛋白乙酰化修饰相关基因的表达情况及临床病例特征热图

图2 各亚组间生存分析及Group3中高表达水平基因与结肠癌微环境细胞的相关性　A为三个亚组结肠癌患者生存分析比较；B为Group3中高表达基因与基质评分、免疫评分、ESTIMATE评分和肿瘤纯度的相关性；C为Group3中高表达基因与免疫细胞浸润程度的相关性

图3 筛选与结肠癌患者预后相关的组蛋白乙酰化修饰基因　A为KAT2A与结肠癌患者无病进展生存期的关系；B为KAT2A与结肠癌患者无进展生存期的关系；C为HDAC8与结肠癌患者无病进展生存期的关系；D为HDAC8与结肠癌患者无进展生存期的关系；E为HDAC8及结肠癌患者病例特征与生存时间的单因素Cox回归分析森林图；F为多因素Cox回归分析森林图；G为基于TCGA数据库比较HDAC8在正常组织和结肠癌组织中的表达水平；H为基于GSE44076数据集比较HDAC8在正常组织和结肠癌组织中的表达水平；I为基于GSE110224数据集比较HDAC8在正常组织和结肠癌组织中的表达水平

图4 HDAC8的GO富集分析

图5 HDAC8与结肠癌中免疫浸润的相关性　A为HDAC8高表达组和低表达组间基质评分、免疫评分、ESTIMATE评分和肿瘤纯度的比较；B为基于CIBERSORT比较HDAC8高-低表达组间的免疫细胞浸润程度；C为基于ssGSEA比较HDAC8高-低表达组间的免疫细胞浸润程度。^*P<0.05；^**P<0.01；^***P<0.001

图6 HDAC8与结肠癌中免疫浸润的相关性散点图　A为HDAC8与免疫细胞浸润程度的相关性；B为HDAC8高低组间T细胞相关功能评分差异；C为HDAC8高低组间幼稚T细胞浸润差异；D为HDAC8高低组间树突状细胞相关功能评分差异；^**P<0.01；^***P<0.001

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Analysis of clinical significance of HDAC8 in colon cancer and its relationship with immune infiltration based on bioinformatics

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Analysis of clinical significance of HDAC8 in colon cancer and its relationship with immune infiltration based on bioinformatics