Identification and validation of necroptosis-related prognostic gene signature and tumor immune microenvironment infiltration characterization in esophageal carcinoma

Abstract

Background Esophageal carcinoma (ESCA) is a common malignancy with a poor prognosis. Previous research has suggested that necroptosis is involved in anti-tumor immunity and promotes oncogenesis and cancer metastasis, which in turn affects tumor prognosis. However, the role of necroptosis in ESCA is unclear. This study aimed to investigate the relationships between necroptosis-related genes (NRGs) and ESCA. Methods and results The clinical data and gene expression profiles of ESCA patients were extracted from The Cancer Genome Atlas (TCGA), and 159 NRGs were screened from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We then identified 52 differentially expressed NRGs associated with ESCA and used them for further analysis. Gene ontology (GO) and KEGG functional enrichment analyses showed that these NRGs were mostly associated with the regulation of necroptosis, Influenza A, apoptosis, NOD-like receptor, and NF-Kappa B signaling pathway. Next, univariate and multivariate Cox regression and LASSO analysis were used to identify the correlation between NRGs and the prognosis of ESCA. We constructed a prognostic model to predict the prognosis of ESCA based on SLC25A5, PPIA, and TNFRSF10B; the model classified patients into high- and low-risk subgroups based on the patient’s risk score. Furthermore, the receiver operating characteristic (ROC) curve was plotted, and the model was affirmed to perform moderately well for prognostic predictions. In addition, Gene Expression Omnibus (GEO) datasets were selected to validate the applicability and prognostic value of our predictive model. Based on different clinical variables, we compared the risk scores between the subgroups of different clinical features. We also analyzed the predictive value of this model for drug sensitivity. Moreover, Immunohistochemical (IHC) validation experiments explored that these three NRGs were expressed significantly higher in ESCA tissues than in adjacent non-tumor tissues. In addition, a significant correlation was observed between the three NRGs and immune-cell infiltration and immune checkpoints in ESCA. Conclusions In summary, we successfully constructed and validated a novel necroptosis-related signature containing three genes (SLC25A5, PPIA, and TNFRSF10B) for predicting prognosis in patients with ESCA; these three genes might also play a crucial role in the progression and immune microenvironment of ESCA.

Bioinformatics analysis and experimental validation of tumorigenic role of PPIA in gastric cancer

“…Our results proved that PPIA was negatively related to ICI in GC. Interestingly, these results were generally consistent with observations reported previously 51 . However, opposite results were observed in hepatocellular carcinoma 26 .…”

High expression of PPIA associates with poor prognosis and tumor immune infiltration of gastric cancer

“…Interestingly, these results were generally consistent with observations reported previously. 47 However, opposite results were observed in hepatocellular carcinoma. 26 Thus, the association between PPIA expression and immune checkpoints was analyzed through GEPIA database.…”

Single-Cell Analyses Reveal Necroptosis’s Potential Role in Neuron Degeneration and Show Enhanced Neuron-Immune Cell Interaction in Parkinson’s Disease Progression

“…Te acccumulation of ferritin can elicit oxidative infammation and NF-κB-TNFα pathway, which may further trigger necroptosis [37]. PPIA (cyclophilin A) acts as an immune infammatory mediator that secretes proinfammatory cytokines induced by oxidative stress [38][39][40][41]. SLC25A4 encodes the adenine nucleotide translocator-1 (ANT1), which is involved in metabolism via the regulation of ATP/ADP release from mitochondria and in regulated cell death as part of the mitochondrial permeability transition pore [42].…”