RESUMEN
Background: Phosphorylation is a critical post-translational modification (PTM) type contributing to colorectal cancer (CRC). The study aimed to construct a nomogram model to predict colon adenocarcinoma (COAD) prognosis based on PTM signatures. Methods: The Cancer Genome Atlas (TCGA) database has been indexed for COAD patients' RNA sequencing, proteomic data, and clinical details. To find potential PTM prognostic signatures, the least absolute shrinkage and selection operator (LASSO) was deployed. Model validation procedures included the use of the Kaplan-Meier (K-M) method, the receiver operating characteristic (ROC) curve, the area under the curve (AUC), and the decision curve analysis (DCA). Additionally, biological enrichment, tumor immune microenvironment, and chemotherapy were also assessed. To validate the model, CRC cells were used in in vitro experiments using western blotting, proliferation assay, colony formation assay, and flow cytometry. Results: The LASSO regression analysis identified 8 PTM sites. Based on the median PTM score, patients were classified into low- and high-risk groups. K-M results showed that high-risk patients had worse prognoses (P<0.001). Our model demonstrated powerful effectiveness and predictive value (TCGA whole group: 1-year AUC =0.611, 2-year AUC =0.574, 3-year AUC =0.627). Additionally, high-risk CRC patients were enriched in KRAS signaling pathways (P=0.01), possessed more robust immune escape capacity (P=0.001, and induced cell-cycle arrest of CRC cells (P<0.01). Conclusions: We established and validated a novel nomogram model related to PTM that can predict prognosis and guide the treatment of COAD.
RESUMEN
Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.