Xu Dafeng, Wang Yu, Wu Jincai, Lin Shixun, Chen Yonghai, Zheng Jinfang
Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.
Geriatric Medicine Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.
Cancer Cell Int. 2021 Nov 24;21(1):621. doi: 10.1186/s12935-021-02326-8.
The aim of this study was to construct a model based on the prognostic features associated with epithelial-mesenchymal transition (EMT) to explore the various mechanisms and therapeutic strategies available for the treatment of metastasis and invasion by hepatocellular carcinoma (HCC) cells.
EMT-associated genes were identified, and their molecular subtypes were determined by consistent clustering analysis. The differentially expressed genes (DEGs) among the molecular subtypes were ascertained using the limma package and they were subjected to functional enrichment analysis. The immune cell scores of the molecular subtypes were evaluated using ESTIMATE, MCPcounter, and GSCA packages of R. A multi-gene prognostic model was constructed using lasso regression, and the immunotherapeutic effects of the model were analyzed using the Imvigor210 cohort. In addition, immunohistochemical analysis was performed on a cohort of HCC tissue to validate gene expression.
Based on the 59 EMT-associated genes identified, the 365-liver hepatocellular carcinoma (LIHC) samples were divided into two subtypes, C1 and C2. The C1 subtype mostly showed poor prognosis, had higher immune scores compared to the C2 subtype, and showed greater correlation with pathways of tumor progression. A four-gene signature construct was fabricated based on the 1130 DEGs among the subtypes. The construct was highly robust and showed stable predictive efficacy when validated using datasets from different platforms (HCCDB18 and GSE14520). Additionally, compared to currently existing models, our model demonstrated better performance. The results of the immunotherapy cohort showed that patients in the low-risk group have a better immune response, leading to a better patient's prognosis. Immunohistochemical analysis revealed that the expression levels of the FTCD, PON1, and TMEM45A were significantly over-expressed in 41 normal samples compared to HCC samples, while that of the G6PD was significantly over-expressed in cancerous tissues.
The four-gene signature construct fabricated based on the EMT-associated genes provides valuable information to further study the pathogenesis and clinical management of HCC.
本研究旨在构建一个基于与上皮-间质转化（EMT）相关的预后特征的模型，以探索可用于治疗肝细胞癌（HCC）细胞转移和侵袭的各种机制及治疗策略。
鉴定EMT相关基因，并通过一致性聚类分析确定其分子亚型。使用limma软件包确定分子亚型之间的差异表达基因（DEG），并对其进行功能富集分析。使用R语言的ESTIMATE、MCPcounter和GSCA软件包评估分子亚型的免疫细胞评分。使用套索回归构建多基因预后模型，并使用Imvigor210队列分析该模型的免疫治疗效果。此外，对一组HCC组织进行免疫组织化学分析以验证基因表达。
基于鉴定出的59个EMT相关基因，将365例肝细胞癌（LIHC）样本分为C1和C2两个亚型。C1亚型大多预后较差，与C2亚型相比免疫评分更高，且与肿瘤进展途径的相关性更强。基于亚型间的1130个DEG构建了一个四基因特征模型。该模型具有高度稳健性，在使用来自不同平台（HCCDB18和GSE14520）的数据集进行验证时显示出稳定的预测效果。此外，与现有模型相比，我们的模型表现更佳。免疫治疗队列的结果表明，低风险组患者具有更好的免疫反应，从而导致更好的患者预后。免疫组织化学分析显示，与HCC样本相比，FTCD、PON1和TMEM45A在41例正常样本中的表达水平显著上调，而G6PD在癌组织中的表达水平显著上调。
基于EMT相关基因构建的四基因特征模型为进一步研究HCC的发病机制和临床管理提供了有价值的信息。
