Department of Gastroenterology, Jingzhou Hospital Affiliated to Yangtze University, Hubei Province, Jing Road 60, Jingzhou, 434000, People's Republic of China.
Department of GI Medicine, Jingmen NO. 1 People's Hospital, Jingmen, 448000, China.
Immunogenetics. 2022 Dec;74(6):539-557. doi: 10.1007/s00251-022-01273-6. Epub 2022 Jul 27.
The Notch pathway is a highly conserved signaling pathway involved in the regulation of cell proliferation and differentiation. However, the relationships between Notch pathway-related genes (NPRGs), immunosuppression, and immunotherapy resistance of hepatocellular carcinoma (HCC) remain unclear. Gene expression data and clinical information were extracted from GSE14520, GSE36376, GSE76427, LIRI-JP, TCGA-LIHC, GSE20140, GSE27150, and IMvigor210 datasets. A consensus clustering analysis based on 10 NPRGs was performed to determine the molecular subtypes, and then a notchScore was constructed based on differentially expressed and prognostic genes between molecular subtypes. Two molecular subgroups with significantly distinct survival and immune cell infiltration were identified. Then, a notchScore was constructed to quantify the Notch index of each patient with HCC. Next, we investigated the correlations between the clinical characteristics and the notchScore using logistic regression. Furthermore, multivariate Cox analysis showed that a high notchScore was an independent predictor of poor overall survival (OS) in the TCGA and LIRI-JP datasets and was associated with higher pathological stages. Additionally, a high notchScore was associated with higher immune cells, higher ESTIMATE score, higher immune score, higher stromal score, higher immune checkpoint, and lower tumor purity, which was consistent with the "immunity tidal model theory." Importantly, a high notchScore was sensitive to immunotherapy. Additionally, GSEA indicated that several GO and KEGG items associated with apoptosis, immune-related pathways, and cell cycle signal pathways were significantly enriched in the high notchScore phenotype pathway. Our findings propose that a high notchScore is a prognostic biomarker and correlates with immune infiltration and sensitivity to immunotherapy in HCC.
Notch 通路是一个高度保守的信号通路，参与细胞增殖和分化的调节。然而，Notch 通路相关基因（NPRGs）、免疫抑制与肝癌（HCC）免疫治疗耐药之间的关系尚不清楚。从 GSE14520、GSE36376、GSE76427、LIRI-JP、TCGA-LIHC、GSE20140、GSE27150 和 IMvigor210 数据集提取基因表达数据和临床信息。基于 10 个 NPRGs 进行共识聚类分析，以确定分子亚型，然后根据分子亚型之间差异表达和预后基因构建 notchScore。鉴定出两个具有显著不同生存和免疫细胞浸润的分子亚群。然后，构建了一个 notchScore 来量化每个 HCC 患者的 Notch 指数。接下来，我们使用逻辑回归研究了临床特征与 notchScore 之间的相关性。此外，多变量 Cox 分析表明，高 notchScore 是 TCGA 和 LIRI-JP 数据集中总生存期（OS）不良的独立预测因子，与较高的病理分期相关。此外，高 notchScore 与较高的免疫细胞、较高的 ESTIMATE 评分、较高的免疫评分、较高的基质评分、较高的免疫检查点和较低的肿瘤纯度相关，这与“免疫潮汐模型理论”一致。重要的是，高 notchScore 对免疫治疗敏感。此外，GSEA 表明，与凋亡、免疫相关途径和细胞周期信号途径相关的几个 GO 和 KEGG 项目在高 notchScore 表型途径中显著富集。我们的研究结果表明，高 notchScore 是一个预后生物标志物，与 HCC 中的免疫浸润和对免疫治疗的敏感性相关。
