Identification of Key Functional Modules and Immunomodulatory Regulators of Hepatocellular Carcinoma.

Ding Luo,Gang Chen,Xiang Zhang,Xiao-Kai Li,Xiao-Jie Lu

doi:10.1155/2021/1801873

Abstract

Despite the advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfactory due to postsurgical recurrence and treatment resistance. Therefore, it is important to reveal the mechanisms underlying HCC and identify potential therapeutic targets against HCC, which could facilitate the development of novel therapies. Based on 12 HCC samples and 12 paired paracancerous normal tissues, we identified differentially expressed mRNAs and lncRNAs using the “limma” package in R software. Moreover, we used the weighted gene coexpression network analysis (WGCNA) to analyze the expression data and screened hub genes. Furthermore, we performed pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In addition, the relative abundance of a given gene set was estimated by single-sample Gene Set Enrichment Analysis. We identified 687 differentially expressed mRNAs and 260 differentially expressed lncRNAs. A total of 6 modules were revealed by WGCNA, and MT1M and MT1E genes from the red module were identified as hub genes. Moreover, pathway analysis revealed the top 10 enriched KEGG pathways of upregulated or downregulated genes. Additionally, we also found that CD58 might act as an immune checkpoint gene in HCC via PD1/CTLA4 pathways and regulate the levels of tumor-infiltrating immune cells in HCC tissues, which might be an immunotherapeutic target in HCC. Our research identified key functional modules and immunomodulatory regulators for HCC, which might offer novel diagnostic biomarkers and/or therapeutic targets for cancer immunotherapy.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the fourth leading cause of cancerrelated death globally, which has posed a substantial financial and health burden [1]
There was a negative correlation between MT1E expression and the infiltration of B cells, CD4+ T cells, and macrophages, while the expression of MT1M was positively associated with the infiltration of B cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. These results indicated that MT1E and MT1M might play an important role in regulating immune infiltration in HCC (Figure 6(g)
weighted gene coexpression network analysis (WGCNA) revealed a total of 6 modules associated with HCC, and MT1M and MT1E from the red module were identified as hub genes

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the fourth leading cause of cancerrelated death globally, which has posed a substantial financial and health burden [1]. The complex mechanisms underlying the initiation and progression of HCC make it challenging to develop novel therapeutic strategies. Accumulating studies reveal the critical roles of immune cells in the initiation, metastasis, and recurrence of HCC [3, 4]. Multiple regulatory molecules could inhibit the antitumor activity of tumor-associated immune cells, resulting in immune escape [5,6,7]. As a strategy to normalize the antitumor immune responses against cancer cells, cancer immunotherapy has achieved clinical success in the last five years and revolutionized the treatment landscape of HCC [8]. It is necessary to reveal the Journal of Immunology Research underlying mechanisms of HCC and identify potential therapeutic targets, with an emphasis on immunomodulatory regulators

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Conclusion