Identification and Characterization of an Ageing-Associated 13-lncRNA Signature That Predicts Prognosis and Immunotherapy in Hepatocellular Carcinoma

Abstract

Background. In cancer pathology, cell senescence not only alters cell function but also reshapes the immune microenvironments in tumours. However, the association between cell senescence, tumour microenvironment, and disease progression of hepatocellular carcinoma (HCC) is yet to be fully understood. Therefore, the role of cell senescence-related genes and long noncoding RNAs (lncRNAs) in evaluating the clinical prognosis and immune cell infiltration (ICI) of HCC patients requires further investigation. Methods. The limma R package was utilised to investigate differentially expressed genes according to the multiomics data. The CIBERSORT R package was utilised to assess ICI, and unsupervised cluster analysis was conducted using the R software’s ConsensusClusterPlus package. A polygenic prognostic model of lncRNAs was constructed by conducting univariate and least absolute shrinkage and selection operator (Lasso) cox proportional-hazards regression analyses. The time-dependent receiver operating characteristic (ROC) curves were used for validation. We utilised the survminer R package to evaluate the tumour mutational burden (TMB). Moreover, the gene set enrichment analysis (GSEA) helped in pathway enrichment analysis, and the immune infiltration level of the model was evaluated using the IMvigor210 cohort. Results. The identification of 36 prognosis-related genes was achieved based on their differential expression between healthy and liver cancer tissues. Liver cancer individuals were categorised into 3 independent senescence subtypes using the gene list, revealing considerable survival differences (variations). We observed that the prognosis of patients in the ARG-ST2 subtype was substantially better as compared to that in the ARG-ST3 subtype. Differences were observed in gene expression profiles among the three subtypes, with the differentially expressed genes predominantly associated with cell cycle control. The enrichment of upregulated genes in the ARG-ST3 subtype was observed in pathways related to biological processes, for instance, organelle fission, nuclear division, and chromosome recombination. ICI in the ARG-ST1 and ARG-ST2 subtypes, with relatively better prognosis, was substantially higher as compared to the ARG-ST3 subtype. Furthermore, a risk-score model, which can be employed as a reliable prognostic factor in an independent manner for individuals suffering from liver cancer, was constructed based on 13 cell senescence-related lncRNAs (MIR99AHG, LINC01224, LINC01138, SLC25A30AS1, AC006369.2, SOCS2AS1, LINC01063, AC006037.2, USP2AS1, FGF14AS2, LINC01116, KIF25AS1, and AC002511.2). The individuals with higher risk scores had noticeably poor prognoses in contrast with those having low-risk scores. Moreover, increased levels of TMB and ICI were observed in individuals with low-risk scores and gaining more benefit from immune checkpoint therapy. Conclusion. Cell senescence is an essential factor in HCC onset and progression. We identified 13 senescence-related lncRNAs as HCC prognostic markers, which can help understand their function in the onset and progression of HCC and guide clinical diagnosis and treatment.