RBM15B Promotes Hepatocellular Carcinoma Progression via IGF2BP1-Mediated ITSN2 mRNA Stabilization

Abstract

Abstract Background: N6-methyladenosine (m6A), the most abundant form of RNA chemical methylation, is aberrantly expressed in hepatocellular carcinoma (HCC), where it affects multiple biological processes including targeted RNA splicing, transport, degradation, stabilization, and translation. Method: The RNA-binding motif protein 15 B (RBM15B) is a pivotal coordinator of m6A activation, such as alternative splicing of mRNA. We investigated the biological effects and potential mechanisms of action of RBM15B in HCC using TCGA database, in-vitro and in vivo assays, and Merip-seq. Results: High levels of RBM15B, which predicts a poor prognosis, have been identified in patients with HCC. RBM15B promotes HCC propagation and invasion in vitro and in vivo. RBM15B regulates the m6A of intersectin2 (ITSN2) mRNA via insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1)-facilitated stabilization of ITSN2 mRNA. ITSN2 depletion rescued the tumor-promoting phenotype induced by RBM15B overexpression. Conclusion: In summary, RBM15B-regulated m6A in ITSN2 facilitates HCC progression via IGF2BP1-guided stabilization of ITSN2 mRNA. Our study illustrates the importance of the RBM15B-IGF2BP1-ITSN2 regulatory axis based on m6A activity and provides new insights into epi-transcriptomic maladjustments of initiation and metastasis in HCC.