Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes the prognostic prediction challenging. As part of the active cross-talk between the tumor and the host, inflammatory response in the tumor or its microenvironment could affect prognosis. However, the prognostic value of inflammatory response-related genes in HCC remains to be further elucidated.
Methods: In this study, the mRNA expression profiles and corresponding clinical data of HCC patients were downloaded from the public database. The least absolute shrinkage and selection operator Cox analysis was utilized to construct a multigene prognostic signature in the TCGA cohort. HCC patients from the ICGC cohort were used for validation. Kaplan Meier analysis was used to compare the overall survival (OS) between high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS. Single-sample gene set enrichment analysis was utilized to calculate the immune cell infiltration score and immune related pathway activity. Gene set enrichment analysis was implemented to conduct GO terms and KEGG pathways. The qRT-PCR and immunohistochemistry were utilized to perform the mRNA and protein expression of prognostic genes between HCC tissues and normal liver tissues respectively.
Results: An inflammatory response-related gene signature model was constructed by LASSO Cox regression analysis. Compared with the low-risk group, patients in the high-risk group showed significantly reduced OS. Receiver operating characteristic curve analysis confirmed the predictive capacity of the prognostic gene signature. Multivariate Cox analysis revealed that the risk score was an independent predictor for OS. Functional analysis indicated that immune status was definitely different between two risk groups, and cancer-related pathways were enriched in high-risk group. The risk score was significantly correlated with tumor grade, tumor stage and immune infiltrate types. The expression levels of prognostic genes were significantly correlated with sensitivity of cancer cells to anti-tumor drugs. Furthermore, the expression of prognostic genes showed significant difference between HCC tissues and adjacent non-tumorous tissues in the separate sample cohort.
Conclusion: A novel signature constructed with eight inflammatory response-related genes can be used for prognostic prediction and impact the immune status in HCC. Moreover, inhibition of these genes may be a therapeutic alternative.
Keywords: drug sensitivity; gene signature; hepatocellular carcinoma; immune status; inflammatory response; overall survival; tumor microenvironment.
Copyright © 2021 Lin, Xu, Miao and Yu.