E3 Ubiquitin Ligase MDM2 Promotes Growth and CD8 + T Cell Dysfunction in Gastric Cancer Through Degradation of SST

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Abstract
Aim: To figure out the role and molecular mechanism of SST in the progression of GC. Methods: GC microarray data GSE118916 were downloaded from the GEO database. Then, the module‐related genes and differentially expressed genes (DEGs) in GC were respectively screened by weighted gene co‐expression network analysis (WGCNA) analysis and limma 3.62.2. The protein–protein interaction (PPI) network was constructed to identify the core genes. After ubibrowser1.0 prediction, interaction between MDM2 and SST was verified using co‐immunoprecipitation (CoIP) assay and GST pull‐down assay. The biological role of MDM2 and SST on GC tumor growth was measured using the xenograft tumor model in vivo. Results: A total of 250 overlapping DEGs were identified using 1673 module‐related genes from WGCNA and 322 DEGs from the GSE118916 database. PPI network identified 17 candidate core genes of GC, which were mainly enriched in gastric acid secretion, collecting duct acid secretion, oxidative phosphorylation, histidine metabolism, fat digestion and absorption, metabolic pathways, and neuroactive ligand‐receptor interaction. One hub gene, SST, was identified according to the machine learning algorithms. SST expression was decreased in GC patients and cells, and its overexpression repressed GC cell proliferation and CD8 + T cell apoptosis, and promoted GC cell apoptosis and CD8 + T cell proliferation. Mechanistically, MDM2 could mediate ubiquitination and destabilization of SST in GC cells. MDM2 knockdown suppressed tumor growth by regulating SST in vivo. Conclusion: MDM2 could facilitate the growth and CD8 + T cell dysfunction in GC through advancing the ubiquitination degradation of SST, which provides a promising therapeutic target for GC treatment.

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