SHP2 in TAMs promoted the survival of gastric adenocarcinoma via suppressing the P38/ERK1/2/SP1/BRD4/STING induced inflammation and ROS

BackgroundIt is well established that tumor-associated macrophages (TAMs) are crucial to the development of tumors. Here, we looked into how SHP2 and M2/M1 macrophages affected gastric cancer.MethodsBulk RNA-seq analysis was conducted using the GSE118916 dataset from the GEO database to screen for differentially expressed genes, and GO, KEGG enrichment analysis, and immune cell infiltration correlation analysis were performed. We also used PMA to differentiate THP-1 cells (M0 macrophages). To simulate the association between gastric adenocarcinoma and TAMS, M0 macrophages were co-cultured with AGS (human gastric adenocarcinoma cells). To mimic the advanced stage of gastric adenocarcinoma the co-cultured cells were cultured in 1% O2 low serum and low sugar. SHP2 overexpression, SHP2 knockdown, and SP1 inhibitor BDR4 inhibitor JQ-1 were used to examine the effects of SHP2, SP1, and BRD4 on macrophage polarization and cancer cell death, migration, and invasion.ResultsBulk RNA-seq analysis revealed that differentially expressed genes in gastric cancer were mainly enriched in extracellular matrix organization and adhesion-related pathways. Macrophages showed significant positive correlation with activated dendritic cells in the immune infiltration analysis. SHP2 overexpression inhibited the expression of p-P38, p-ERK1/2, p-SP1, BRD4, FOXM1, STING, NRLP3, and inflammation- and ROS-related cytokines IL-1β, TNFα, and MDA, and SOD, and the expression of M2 polarization-associated proteins, Arg-1 and Cathepsin K. The aforementioned proteins’ expression was greatly enhanced by SHP2. the aforementioned proteins’ expression. P-SP1 was significantly inhibited under the action of SP1 inhibitor, in addition, STING, NRLP3 and ROS-related proteins IL-1β, TNFα and MDA, SOD expression, M2 polarization-related proteins Arg-1, Cathepsin K. The expression of the aforementioned proteins was markedly decreased by the combination of SP1 inhibitor and BRD4 inhibitor. Additionally, there was an increase in cancer cell invasion, migration, and death.ConclusionSHP2 in TAMs promotes gastric adenocarcinoma survival by inhibiting P38/ erk1 /SP1/BRD4/STING-induced inflammation and ROS.