Stanniocalcin 1 promotes gastric cancer progression by activating the PI3K/AKT pathway and inducing M2 macrophage polarization via the JAK2/STAT3/lL-10 axis

BACKGROUND: Stanniocalcin 1 (STC1) is an immune checkpoint in macrophages that promotes tumor immune evasion and resistance to immunotherapy. This study aims to elucidate the functional role and underlying regulatory mechanisms of STC1 in gastric cancer (GC) and its associated tumor microenvironment. METHODS: GC cells were transfected with STC1-knockout (KO-STC1) and overexpression (OE-STC1) plasmids. To evaluate the effect of STC1 expression on the polarization of tumor-associated macrophages (TAMs) into the M2 phenotype, KO-STC1 GC cells were cocultured with M0 macrophages. To understand whether STC1 modulates the malignant behaviors of GC cells through the promotion of TAM polarization into the M2 state and elucidate the regulatory mechanisms, Cell Counting Kit-8 (CCK8), Transwell, Western blotting (WB), and enzyme-linked immunosorbent assays (ELISA) were performed. RESULTS: In patients with GC, the expression level of STC1 markedly increased (P <0.0001), which resulted in an unfavorable clinical prognosis. Dysregulated STC1 bound integrin subunit beta 6 (ITGB6) to modulate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway in vitro and in vivo, which influenced the malignant behavior of GC cells, including proliferation, migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT). STC1 modulated the polarization of TAMs into the M2 state, which affected the proliferation, invasion, and EMT of GC cells. KO-STC1 GC cells cocultured with M0 macrophages inhibited the progression of GC through the inactivation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in TAMs, which suppressed M2 polarization and the secretion of interleukin-10 (IL-10). CONCLUSIONS: STC1 binds ITGB6 and modulates the progression of GC through the activation of the PI3K/AKT pathway, polarization of TAMs into the M2 state, and secretion of IL-10 via the JAK2/STAT3 pathway. This study may imply that STC1 has the potential to be a new target to suppress the development of GC.