Inflammation-Related Gene ADH1A Regulates the Polarization of Macrophage M1 and Influences the Malignant Progression of Gastric Cancer.

Abstract

Gastric cancer (GC) is a malignant tumor originating from the gastric mucosa epithelium, and there is a low survival rate of GC patients after treatment, with a poor prognostic outcome. The inflammatory response within the tumor microenvironment plays an important role in GC progression. We downloaded GC-related datasets and inflammation-related genes from GEO, TCGA and MSigDB databases, performed differential analysis, protein-protein interaction analysis, immunoinfiltration analysis and Lasso analysis to screen inflammation-related hub genes affecting GC progression, and carried out qRT-PCR for validation. In order to explore the role of ADH1A, we constructed overexpressed plasmids, treated GC cells with cGMP/PKG pathway agonist 8-Br-cGMP, and tested cell functions with CCK8, EdU, Transwell, scratch assay and other experiments. On this basis, GC cells were co-cultured with monocyte THP-1 to explore the effect of ADH1A on the polarization of macrophages. ADH1A was significantly decreased in GC cells, and its expression trend was consistent with the results of bioinformatics analysis. Therefore, we chose ADH1A for subsequent functional validation. Overexpression of ADH1A in GC cells revealed ADH1A's role in inhibiting the activity, proliferation, migration and invasion of GC cells, promoting apoptosis and secretion of IL-6, IFN-γ, CCL5 and CSF2, and facilitating the transformation of macrophages to a pro-inflammatory M1 phenotype. ssGSEA results demonstrated the potential involvement of ADH1A in the cGMP/PKG signaling pathway, and significant changes in the expression of proteins related to the cGMP/PKG signaling pathway. The use of the cGMP/PKG signaling pathway agonist 8-Br-cGMP in ADH1A-overexpressing GC cells substantiated ADH1A's capacity to inhibit the cGMP/PKG signaling pathway, thereby suppressing the malignant progression of GC and promoting the transformation of macrophages to a pro-inflammatory M1 phenotype. ADH1A is able to influence the malignant progression of GC and the transformation of macrophages to the pro-inflammatory M1 phenotype through the cGMP/PKG signaling pathway.