Abstract
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.
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Data availability
All data used in the study can be downloaded from the TCGA data repository (https://portal.gdc.cancer.gov/repository; accessed 26 May 2021), ICGC data (https://icgc.org/; accessed 26 May 2021) and the GEO database (https://www.ncbi.nlm.nih.gov/gds/?term = ; accessed 26 May 2021).
Change history
06 October 2022
The Affiliation of the corresponding author "Shitao Xia" has been updated.
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Peng Ma and Shitao Xia designed the study, performed statistical analysis, and drafted the manuscript. Chuanxin Zou helped to draft the manuscript. Shitao Xia conceived the study, participated in its design and coordination, and helped draft the manuscript. All authors read and approved the final manuscript.
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Ma, P., Zou, C. & Xia, S. Oncogenic signaling pathway mediated by Notch pathway-related genes induces immunosuppression and immunotherapy resistance in hepatocellular carcinoma. Immunogenetics 74, 539–557 (2022). https://doi.org/10.1007/s00251-022-01273-6
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DOI: https://doi.org/10.1007/s00251-022-01273-6