Zuo Bangyou, Kuai Jing, Long Junyu, Bian Jin, Yang Xu, Yang Xiaobo, Xun Ziyu, Li Yiran, Sun Huishan, Sang Xinting, Zhao Haitao
Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Hepatobiliary Surgery, Weifang People's Hospital, Weifang, China.
Ann Transl Med. 2022 Aug;10(15):817. doi: 10.21037/atm-21-4400.
Exosomes are involved in cell-to-cell communication, neovascularization, cancer metastasis, and drug resistance, which all play an important role in the occurrence and progression of hepatocellular carcinoma (HCC). Because there are few mechanistic studies about the function of exosomes in HCC, the goals of this study were to identify exosome-related genes in HCC, to establish a reliable prognostic model for HCC, and to explore underlying mechanisms.
The exoRBase and The Cancer Genome Atlas (TCGA) databases were used to analyze differentially expressed genes (DEGs). Cox regression and least absolute shrinkage and selection operator analyses were used to identify DEGs closely related to the overall survival of patients with HCC. An exosome-related prognostic model was then constructed in TCGA and validated in the International Cancer Genome Consortium database. A nomogram was developed to predict survival. CIBERSORT was used to estimate the abundance of different types of immune cells. Immunotherapy-related DEGs were used to predict the effect of immunotherapy.
Forty-eight exosome-related DEGs were obtained; of them, five [exportin 1 (), lysosomal thiol reductase (), F-box protein 16 (), calmodulin 1 (), MORC family CW-type zinc finger 3 ()] were selected to construct a predictive model. Patients with HCC were then divided into low- and high-risk groups using the best cut-off value, as determined by the X-tile software. Prognosis was significantly poorer in the high-risk than in the low-risk group (P=0.009; hazard ratio =2.65). Features related to exosomes were found to positively regulate immune response. Further analysis showed a higher risk score was associated with higher expression of immune checkpoint molecules, including programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell Ig and ITIM domain (TIGIT), and indoleamine-2,3-dioxygenase 1 (IDO1).
This study has identified a novel signature based on exosome-related genes that has potential as a prognostic biomarker for HCC. Our research provides an immunological perspective for the development of precision treatment for HCC.
外泌体参与细胞间通讯、新血管生成、癌症转移和耐药性，这些在肝细胞癌（HCC）的发生和发展中均起重要作用。由于关于外泌体在HCC中功能的机制研究较少，本研究的目的是鉴定HCC中与外泌体相关的基因，建立可靠的HCC预后模型，并探索潜在机制。
使用外泌体相关数据库（exoRBase）和癌症基因组图谱（TCGA）数据库分析差异表达基因（DEG）。采用Cox回归和最小绝对收缩与选择算子分析来鉴定与HCC患者总生存期密切相关的DEG。然后在TCGA中构建外泌体相关预后模型，并在国际癌症基因组联盟数据库中进行验证。开发列线图以预测生存期。使用CIBERSORT估计不同类型免疫细胞的丰度。利用与免疫治疗相关的DEG预测免疫治疗效果。
获得48个与外泌体相关的DEG；其中，选择5个基因[输出蛋白1（）、溶酶体硫醇还原酶（）、F盒蛋白16（）、钙调蛋白1（）、MORC家族CW型锌指蛋白3（）]构建预测模型。然后使用X-tile软件确定的最佳临界值将HCC患者分为低风险组和高风险组。高风险组的预后明显比低风险组差（P = 0.009；风险比 = 2.65）。发现与外泌体相关的特征可正向调节免疫反应。进一步分析表明，较高的风险评分与免疫检查点分子的高表达相关，包括程序性死亡配体1（PD-L1）、程序性死亡配体2（PD-L2）、T细胞免疫球蛋白和ITIM结构域（TIGIT）以及吲哚胺-2,3-双加氧酶1（IDO1）。
本研究基于与外泌体相关的基因鉴定了一种新的特征，其有潜力作为HCC的预后生物标志物。我们的研究为HCC精准治疗的发展提供了免疫学视角。
