Bioinformatics-Based Identification and Clinical Validation of CHST1 as a Potential Prognostic Gene Associated With EMT in Gastric Cancer

Background: Gastric Cancer (GC) is among the most frequently diagnosed malignancies worldwide. Identifying novel therapeutic targets is of great significance.

Methods: GC-related RNA-seq data and matched clinical information were retrieved from the publicly available The Cancer Genome Atlas (TCGA) database. The epithelial-mesenchymal transition (EMT) scores of GC and normal tissues were calculated using the gene set variation analysis (GSVA) package. Weighted gene coexpression network analysis (WGCNA) was applied to identify modules associated with EMT. The survival and clinical relevance of EMT-related core genes were analyzed, and carbohydrate sulfotransferase 1 (CHST1) was selected for further investigation. CHST1 expression was validated in patient-derived GC tissues and GC cell lines. Subsequently, CHST1 expression and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway activity were modulated in AGS cells to evaluate their effects on cell proliferation, Apoptosis, migration, and EMT. In vivo experiments were conducted to elucidate the involvement of CHST1 expression in GC growth.

Results: The EMT score was markedly higher in GC tissues than in normal tissues. Within the EMT-related module, 7 hub genes (CHST1, GPR176, OLFML2B, P4HA3, PDGFRB, SPARC, and VCAN) were closely associated with GC prognosis. CHST1 expression was strongly correlated with both the EMT score and T stage. As revealed by survival analysis, patients with high CHST1 expression had shorter overall survival than those with low expression. A marked up-regulation of CHST1 protein expression was observed in clinical GC tissues compared with normal tissues. In vitro, CHST1 expression was significantly elevated in GC cell lines. Inhibiting CHST1 expression in AGS and HGC27 cells suppressed cell proliferation, migration, as well as EMT, while simultaneously promoting Apoptosis. In AGS cells, CHST1 regulated cell proliferation, Apoptosis, migration, and EMT through the MAPK/ERK signaling pathway. In vivo, CHST1 significantly promoted GC growth and increased the activity of the MAPK/ERK signaling pathway.

Conclusion: CHST1 is highly expressed in GC and may influence GC progression by regulating the MAPK/ERK signaling pathway.

CHST1; epithelial-mesenchymal transition; gastric cancer; prognosis.