Identification of CERS5 as a novel biomarker for prognosis and immunity in hepatocellular carcinoma: a bioinformatics analysis and functional validation study

Abstract

Objective Hepatocellular carcinoma (HCC) is an extremely deadly cancer with few effective therapeutic options available. Ceramide synthases (CERS), a family of enzymes that regulate sphingolipid metabolism, have been suggested to play a role in cancer initiation and progression. Whereas the specific functions of CERS in HCC pathogenesis have not yet been fully elucidated. Methods The TCGA and ICGC databases were employed to analyze the expression levels and clinical relevance of CERS genes in HCC. Functional enrichment analyses were performed to identify pathways and functions associated with CERS5. The correlation between CERS5 and the tumor immune microenvironment was investigated. The mutation landscape and immunotherapy efficacy were evaluated. Functional experiments in vitro were conducted to assess CERS5’s impact on HCC cell proliferation and invasion. Results Aberrant expression of the CERS family was detected not only in HCC but also in other cancers, and has been linked to both overall survival and disease-free survival. Among the CERS family members, CERS5 was identified as the only prognosis-related gene, with up-regulated in HCC validated in the ICGC database and clinical tissue samples. Higher expression levels of CERS5 were associated with a poorer prognosis as well as an advanced pathologic stage and grade, as confirmed by the TCGA and ICGC databases. Besides, a prognostic nomogram combining pathologic stage, tumor status, and the expression of CERS5 was established and further validated, which suggested a favorable value for prognosis prediction. Functional enrichment analyses showed that the overexpression of CERS5 resulted in enriched pathways associated with carcinogenesis, drug metabolism, the PI3K/AKT/mTOR signaling pathway, and cancer immune-related pathways. In addition, the overexpression of CERS5 correlated positively with the expression of genes associated with immunogenic cell death modulators and immune checkpoints, levels of immune cell infiltration, and immunotherapy response, which was featured in an immunologically “hot” environment in the tumor microenvironment. Finally, the functional experiments showed that CERS5 knockdown has been shown to inhibit the growth and invasion of hepatocellular carcinoma, potentially through targeting the PI3K/AKT/mTOR signaling pathway. Conclusions Based on our findings, CERS5 appears to have great potential as both a precise prognostic biomarker and a novel therapeutic target in HCC.