IGF2BP1 promotes gastric cancer progression by stabilizing HS6ST2 mRNA in an N6-methyladenosine-dependent manner
BACKGROUND Gastric cancer (GC) remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis, which highlights an urgent need to identify effective biomarkers and therapeutic targets. N6-methyladenosine (m6A) modification and its reader proteins play a crucial role in tumorigenesis. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) participates in carcinogenesis and serves as a reader of m6A. However, its exact function and the underlying molecular mechanisms in the progression of GC remain unknown. AIM To investigate the role of IGF2BP1 in the progression of GC. METHODS The IGF2BP1 expression in GC tissues was assessed via immunohistochemistry and correlated with clinicopathological characteristics. Gain-of-function and loss-of-function experiments were performed to explore the functional roles of IGF2BP1 and its potential downstream target in GC cells and a nude mouse xenograft model. Cell proliferation, migration, and invasion were assessed using cell counting kit-8, wound-healing, and Transwell assays. RNA sequencing, methylated RNA immunoprecipitation quantitative polymerase chain reaction, and dual-luciferase reporter assays were conducted to elucidate the molecular mechanisms involved. RESULTS The IGF2BP1 was significantly upregulated in GC tissues and was positively associated with lymph node metastasis and poor overall survival. Functionally, IGF2BP1 knockdown inhibited GC cell proliferation, migration, and invasion in vitro and attenuated tumor growth in vivo . Integrated multi-omics analysis identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a key downstream target of IGF2BP1. IGF2BP1 recognized and bound to m6A-modified sites within HS6ST2 mRNA, thereby enhancing its stability in an m6A-dependent manner. Rescue experiments confirmed that HS6ST2 mediated the oncogenic effects of IGF2BP1. Additionally, HS6ST2 knockdown inhibited the malignant characteristics of GC cells and triggered apoptosis, which was associated with inactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. CONCLUSION These findings demonstrated that IGF2BP1 drives GC progression by stabilizing HS6ST2 mRNA via m6A modification. The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic intervention for GC.