Identification of Prognostic Genes in the Tumor Microenvironment of Hepatocellular Carcinoma

Shixin Xiang, Jing Li, Jing Shen, Yueshui Zhao, Xu Wu, Mingxing Li, Xiao Yang, Parham Jabbarzadeh Kaboli, Fukuan Du, Yuan Zheng, Qinglian Wen, Chi Hin Cho, Tao Yi*, Zhangang Xiao*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

47 Citations (Scopus)


Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The efficacy of immunotherapy usually depends on the interaction of immunomodulation in the tumor microenvironment (TME). This study aimed to explore the potential stromal-immune score-based prognostic genes related to immunotherapy in HCC through bioinformatics analysis. Methods: ESTIMATE algorithm was applied to calculate the immune/stromal/Estimate scores and tumor purity of HCC using the Cancer Genome Atlas (TCGA) transcriptome data. Functional enrichment analysis of differentially expressed genes (DEGs) was analyzed by the Database for Annotation, Visualization, and Integrated Discovery database (DAVID). Univariate and multivariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were performed for prognostic gene screening. The expression and prognostic value of these genes were further verified by KM-plotter database and the Human Protein Atlas (HPA) database. The correlation of the selected genes and the immune cell infiltration were analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm and Tumor Immune Estimation Resource (TIMER). Results: Data analysis revealed that higher immune/stromal/Estimate scores were significantly associated with better survival benefits in HCC within 7 years, while the tumor purity showed a reverse trend. DEGs based on both immune and stromal scores primarily affected the cytokine–cytokine receptor interaction signaling pathway. Among the DEGs, three genes (CASKIN1, EMR3, and GBP5) were found most significantly associated with survival. Moreover, the expression levels of CASKIN1, EMR3, and GBP5 genes were significantly correlated with immune/stromal/Estimate scores or tumor purity and multiple immune cell infiltration. Among them, GBP5 genes were highly related to immune infiltration. Conclusion: This study identified three key genes which were related to the TME and had prognostic significance in HCC, which may be promising markers for predicting immunotherapy outcomes.

Original languageEnglish
Article number653836
Number of pages14
JournalFrontiers in Immunology
Publication statusPublished - 7 Apr 2021

Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

User-Defined Keywords

  • ESTIMATE algorithm
  • Hepatocellular carcinoma
  • Prognosis
  • TCGA
  • tumor microenvironment


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