Identification of a PANoptosis-related long noncoding rna risk signature for prognosis and immunology in colon adenocarcinoma.

backgroundPANoptosis, a complex programmed cell death (PCD) pathway that includes apoptosis, pyroptosis and necroptosis, is significantly involved in the progression of cancers. Long noncoding RNAs (lncRNAs) play crucial roles in PCD. However, the predictive value of PANoptosis-related lncRNAs (PRlncRNAs) for colon adenocarcinoma (COAD) has not been established.

methodsGene expression data and clinical characteristics of patients with COAD were obtained from The Cancer Genome Atlas database. Differential expression analysis and Pearson correlation analysis were used to identify PRlncRNAs. In addition to least absolute shrinkage and selection operator, univariate and multivariate Cox regression analyses were employed to obtain PRlncRNAs for constructing a risk signature. Patients with COAD in the training set, testing set and entire set were stratified into high- and low-risk groups for further comparison of survival prognosis, using the median risk score as the cut-off point. Time-dependent receiver operating characteristic curves, a nomogram and multivariate Cox regression analysis were conducted to validate the risk signature in the testing set and the entire set. In addition, critical pathways, immune infiltration cells, immune checkpoint-related genes, Tumor Immune Dysfunction and Exclusion (TIDE) scores and antitumour drugs were compared between the two risk groups in the entire set. Correlations between ferroptosis, cuproptosis, disulfidptosis and the PRlncRNA risk score were evaluated. Finally, a competitive endogenous RNA (ceRNA) network was established, and enrichment analysis of the predicted mRNAs was performed using Gene Ontology (GO) analysis. The Kaplan-Meier plotter database was used as an external database to confirm the accuracy of the risk signature in predicting patient prognosis. Additionally, small interfering RNA (siRNA), a cell counting kit- 8 assay, a cell colony formation assay, quantitative polymerase chain reaction (qPCR) and an apoptosis assay were further employed to investigate the roles of AP003555.1 in colon cancer.

resultsA risk signature comprising four PRlncRNAs (LINC01133, FOXD3-AS1, AP001066.1, and AP003555.1) was developed to predict the prognosis of patients with COAD. Kaplan‒Meier curves demonstrated significant differences in prognosis between the high- and low-risk groups across the three sets. Multivariate Cox regression analysis confirmed that the risk signature was an independent prognostic factor across the three sets. A nomogram, receiver operating characteristic curves and calibration curves indicated strong confidence in the risk signature. Using the CIBERSORT algorithm and gene set enrichment analysis, variations in infiltrating immune cells and immune processes were observed between the two risk groups. Furthermore, TIDE algorithm suggested that the high-risk group exhibited a lower risk of immunotherapy escape and better immunotherapy outcomes than the low-risk group. Distinct responses to various antitumour drugs were observed between the two risk groups. Additionally, we constructed a ceRNA network based on PRlncRNAs, and GO enrichment analysis of the predicted mRNAs revealed different functions. In addition, the results of the Kaplan‒Meier plotter database revealed that patients who exhibited high levels of LINC01133 and FOXD3-AS1 experienced significantly shorter overall survival than those with low levels of these lncRNAs. Specifically, in terms of functionality, AP003555.1 was found to be highly expressed in colon cancer tissue and promoted viability and proliferation while suppressing the apoptosis of colon cancer cells.

conclusionWe identified a novel risk signature consisting of four PRlncRNAs, which is an independent prognostic indicator for patients with COAD. This PRlncRNA risk signature is potentially relevant for immunotherapy and could serve as a therapeutic target for COAD.