IGF2BP3-GP130-STAT3-WTAP loop promotes the malignant progression in glioblastoma

IGF2BP3, an oncogenic RNA-binding protein, extensively promotes tumor proliferation, metastasis, and immune escape through m6A-dependent RNA stabilization mechanisms, epigenetic regulation, and activation of key signaling pathways. However, the mechanism by which IGF2BP3-mediated m6A modification promotes the malignant progression of GBM requires further investigation.

Bioinformatics was used to explore IGF2BP3 expression and prognosis. CCK8, colony formation, and Transwell assays were used to assess the in vitro impact of IGF2BP3 on tumor malignancy. RIP-qPCR was used to validate IGF2BP3 enrichment in GP130 mRNA. An intracranial orthotopic tumor model was used to validate the tumor-promoting role of IGF2BP3 in vivo.

Aberrant IGF2BP3 expression was associated with poor prognosis in patients with GBM and promoted malignant tumor progression in vivo and in vitro. IGF2BP3 stabilizes GP130 mRNA via m6A modification, activating the STAT3 pathway. STAT3 transcriptionally regulates the WTAP expression.

In this study, we elucidate a novel positive feedback loop in GBM where IGF2BP3 stabilizes m6A-modified GP130 mRNA, activating the JAK2/STAT3 pathway, which subsequently transcriptionally upregulates WTAP, thereby synergistically enhancing m6A modification and tumorigenesis.