Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment.
Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment.
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DOI：
10.3389/fimmu.2022.834606
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发表时间：
2022
影响因子：
7.3
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Li Z;Wang R;Qiu C;Cao C;Zhang J;Ge J;Shi Y
DTL在基因组稳定性中的重要作用已被证实；然而，其预后价值及其与肝细胞癌(HCC)肿瘤免疫的关系仍有待进一步探讨。从GEO、ICGC和TCGA数据库中检索转录和突变数据集以及临床信息。比较TCGA-肝癌队列中DTL高表达组和低表达组的差异表达基因(DEG)。这些基因在KEGG和基因本体论(GO)分析下，以破译DTL基因对肝癌肿瘤细胞生物学行为的影响。根据DTL水平描述和分析患者的生存状态和突变特征。114例肝细胞癌患者的队列(验证队列)进一步证实了DTL在肝细胞癌中的过度表达及其对预后的影响。采用TIMER、GEPIA和TISIDB数据库研究DTL水平与免疫细胞状态和免疫细胞浸润之间的潜在关系。DTL基因在肿瘤组织中的表达高于远处的非恶性肝组织，在肝癌组织中的过表达可促进肝癌细胞的细胞周期和分裂活动。DTL高表达的肝细胞癌患者与低表达的患者相比，临床转归差，体细胞突变多，多因素分析也显示DTL的高表达可作为判断预后的独立生物标志物。此外，DTL基因与浸润性激活的CD8+和CD4+T细胞的标记集呈正相关；然而，这些细胞显示出功能耗尽。由于DTL基因在促细胞增殖过程中的作用，伴随免疫抑制的微环境和T细胞的耗竭，在肝细胞癌中DTL高表达表型的患者预后比DTLlow组差。
The crucial role of DTL has been previously implicated in genomic stability; however, its prognostic value and its relation with tumor immunity in hepatocellular carcinoma (HCC) remain to be further explored. Transcriptional and mutational datasets as well as clinical information were retrieved from the GEO, ICGC, and TCGA databases. Differentially expressed genes (DEGs) were obtained from the comparison of DTLhigh and DTLlow expression groups of the TCGA-HCC cohort. Those genes were under KEGG and gene ontology (GO) analyses to decipher the influence of the DTL gene on the biological behavior of HCC tumor cells. The survival status and mutational characteristics of patients according to DTL levels were depicted and analyzed. The DTL overexpression in HCC and its impact on prognosis were further confirmed by a cohort of 114 HCC patients (validation cohort). The TIMER, GEPIA, and TISIDB databases were adopted to investigate the potential relations between DTL levels and the status of immune cells, as well as immune cell infiltrations. The DTL gene is overexpressed in tumor tissues compared with distant non-malignant liver tissues, and DTL overexpression in HCC would enhance the HCC cells in the activities of cell cycle and division. HCC patients with high DTL expression have unfavorable clinical outcomes and harbor more somatic mutations than those with low DTL expression, and multivariate analysis also revealed that DTL overexpression could act as an independent biomarker for prognosis. Moreover, the DTL gene was positively linked to marker sets of infiltrating activated CD8+ and CD4+ T cells; however, these cells demonstrated to be functionally exhausted. Patients with a DTL overexpression phenotype in HCC have poorer prognosis than those in the DTLlow group due to the role of the DTL gene in the process of pro-cell proliferation, accompanied by the immunosuppressive microenvironment and T cell exhaustion.
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