A ubiquitination-related risk model for predicting the prognosis and immunotherapy response of gastric adenocarcinoma patients

Abstract

Ubiquitination is crucial for the growth of cancer. However, the role of ubiquitination-related genes (URGs) in stomach adenocarcinoma (STAD) remains unclear. Differentially expressed URGs (DE-URGs) were examined in the whole TCGA-STAD dataset, and the prognosis-related genes were discovered from the The Cancer Genome Atlas (TCGA) training set. Prognostic genes were discovered using selection operator regression analysis and absolute least shrinkage (LASSO). A multivariate Cox analysis was further employed, and a polygene-based risk assessment system was established. Signatures were verified using the Gene Expression Omnibus (GEO) database record GSE84433 and the TCGA test set. Using the MEXPRESS dataset, a detailed analysis of gene expression and methylation was carried out. Using the DAVID database, DE-URG function and pathway enrichment was examined. The identified 163 DE-URGs were significantly associated with pathways related to protein ubiquitination, cell cycle, and cancer. A prognostic signature based on 13 DE-URGs was constructed, classifying patients into two risk groups. Compared to low-risk patients, people at high risk had considerably shorter survival times. Cox regression analyses considered prognostic parameters independent of age and risk score and were used to generate nomograms. Calibration curves show good agreement between nomogram predictions and observations. Furthermore, the results of the MEXPRESS analysis indicated that 13 prognostic DE-URGs had an intricate methylation profile. The enhanced Random Forest-based model showed greater efficacy in predicting prognosis, mutation, and immune infiltration. The in vitro validation, including CCK8, EdU, Transwell, and co-culture Transwell, proved that RNF144A was a potent oncogene in STAD and could facilitate the migration of M2 macrophages. In this research, we have created a genetic model based on URGs that can appropriately gauge a patient’s prognosis and immunotherapy response, providing clinicians with a reliable tool for prognostic assessment and supporting clinical treatment decisions.

Keywords

• Ubiquitination
• Stomach adenocarcinoma
• Risk model
• Immune infiltration
• Immunotherapy