https://orcid.org/0000-0002-2885-8741
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Abstract
Introduction
Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.
Methods
A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.
Results
GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.
Conclusion
A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.
Abbreviations
HCC, hepatocellular carcinoma; GRB2, growth factor receptor-bound protein 2; SH3, Src homology 3; TMA, tissue microarray; IHC, immunohistochemistry; qRT-PCR, quantitative real-time polymerase chain reaction; TCGA, The Cancer Genome Atlas; ICGC, International Cancer Genome Consortium; GSEA, gene set enrichment analysis; PPI, protein–protein interaction; TIMER, Tumor Immune Estimation Resource; NK, nature kill cell; ILC, innate lymphoid cell; DC, dendritic cell.
Ethics Approval
This study was approved by the ethics committee of Clinical Medical College, Yangzhou University, China.
Consent for Publication
All of the HCC patients in the study have given their consent to publish their data.
Acknowledgments
YT especially thank these people who gave enough support and encouragement to him.
Author Contributions
(I) Conceptualization: D Bai, C Zhang, Y Tang, J Cao; (II) Study design: D Bai, C Zhang, R Peng; (III) Acquisition of data: Y Tang, J Cao, X MAO, H Tang, D Tu, Y Tang, J Zhou; (IV) Execution: S Jin, R Liu, G Jiang, Q Wang, B Su and Q Wang; (V) Analysis and interpretation Y Tang, C Zhang. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
All the authors declare that they have no competing interests.