IGF2BP3-STAT3-METTL3 axis promotes malignant progression in hepatocellular carcinoma (HCC).

BACKGROUND: Hepatocellular carcinoma (HCC) is often diagnosed in the late stage, with limited effectiveness of traditional treatments and a low overall survival rate. The underlying molecular mechanisms of HCC require further study. METHODS: Differential and survival analyses evaluated IGF2BP3 expression and prognosis. CCK8 and colony formation assays assessed the impact of IGF2BP3 on tumor malignancy. GEO data screened potential substrates modified by IGF2BP3. RIP-qPCR validated N6-methyladenosine (m6A) modification, while animal models confirmed the tumor-promoting effects of IGF2BP3. RESULTS: Abnormally high expression of IGF2BP3 is associated with poor prognosis in HCC. IGF2BP3 activates the JAK2-STAT3 pathway through m6a modification of IL4R mRNA in HCC. Then, STAT3 regulates the nuclear localization of METTL3 through WTAP. CONCLUSION: In this study, we show that IGF2BP3 binds to and stabilizes IL4R mRNA, activating the JAK2/STAT3 pathway. STAT3 enhances METTL3's nuclear retention via WTAP, coordinating the m6A modification of IGF2BP3 in HCC.