SH3 Domain-Binding Glumatic Acid-Rich Protein-Like 3 is closely associated with hyperglycemia and poor outcome in Epstein-Barr Virus-negative Gastric Carcinoma

Abstract

Abstract Background SH3 domain-binding glutamate acid-rich protein-like 3 (SH3BGRL3) has recently been indicated in several human cancers. However, its relationship with gastric cancer (GC) remains exclusive. Methods Using multiple online bioinformatic tools to evaluate the messenger RNA(mRNA) levels of SH3BGRL3 in GC from the database of The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus. RT-qPCR and tissue microarray-based immunohistochemistry were performed to observe SH3BGRL3 expression concerning clinicopathological parameters and outcomes in GC patients. Significantly differentially expressed genes (DEGs) of SH3BGRL3 were enriched and visualized. Meanwhile, the associations between SH3BGRL3 expression and immune infiltrating cells were explored. Results SH3BGRL3 exhibited aberrant expression in tumor tissues compared to the adjacent normal tissues at mRNA levels and protein expression, especially in EBVnGC. Higher SH3BGRL3 expression is significantly associated with increasing TNM staging, tumor budding, perineural invasion, EGFR expression, and a notably higher preoperative blood glucose concentration in clinical specimens. Multivariate analysis revealed that higher SH3BGRL3 expression was an independent adverse prognostic factor for the overall survival of EBVnGC patients (HR = 1.666, p = 0.018). Furthermore, the stratified analysis showed SH3BGRL3 phenotype could refine prognostication in patients. The C-index of the nomogram was 0.740 when combining SH3BGRL3 with other clinicopathological parameters, which indicated a good model for clinical follow-up decisions. Gene functional enrichment analysis revealed that the DEGs of SH3BGRL3 were mainly enriched in regulating ATP metabolism, ATP synthesis, oxidative phosphorylation, and electron transport chain in GC. Higher SH3BGRL3 expression was significantly positively correlated with the infiltrating macrophages in GC. Conclusion SH3BGRL3 was upregulated in GC, particularly in EBVnGC. Higher SH3BGRL3 expression was closely associated with hyperglycemia and poor outcomes in EBVnGC patients, suggesting a potential biomarker and prognostic predictor.