VSIG2 hinders gastric cancer progression by suppressing ANXA2-mediated NF-κB pathway activation

As the fifth most common cancer and the third leading cause of cancer death worldwide, gastric cancer (GC) has long been a serious global health challenge. The purpose of this study was to explore the expression of V-set and immunoglobulin domain containing 2 (VSIG2) in GC and to elucidate its role in GC progression and related mechanisms. Western blot analysis, qRT-PCR and immunohistochemical (IHC) staining are used to detect the expression of VSIG2 in GC cells and tissues. Kaplan-Meier survival curve analysis is performed. The effects of VSIG2 on biological effects related to GC progression in vitro are detected by CCK-8, EdU, Transwell and wound healing assays and in vivo by a nude mouse subcutaneous tumor model and a liver metastasis model. Mechanistically, co-immunoprecipitation, immunofluorescence and ubiquitination experiments are used to explore the regulatory effect of VSIG2 on ANXA2 and the regulatory effect between FBXW10 and ANXA2. VSIG2 is abnormally expressed at low levels in patients with GC and is associated with patient prognosis. Low VSIG2 expression is closely related to tumor size, lymph node metastasis, TNM stage and vascular invasion in GC patients. Functionally, in vitro and in vivo experiments reveal that VSIG2 could inhibit the growth, proliferation and metastasis of GC. Mechanistically, VSIG2 and ANXA2 interact directly in GCs and co-localize at the cell membrane. Further exploration reveals that highly expressed VSIG2 competes with FBXW10 for binding to ANXA2 and relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2 and further inactivate NF-κB, thereby suppressing GC progression. In summary, VSIG2 is expressed at abnormally low levels in patients with GC, and its low expression is associated with poor patient prognosis. VSIG2 can inhibit the proliferation and migration of GC via the ANXA2/NF-κB pathway. This study elucidates a new mechanism by which VSIG2 inhibits GC progression, which may provide a new perspective for the diagnosis and treatment of GC patients.