# RBM15 Enhances 5-Fluorouracil Drug Sensitivity and Suppresses Gastric Cancer Progression by Modulating N6-Methyladenosine Modification of ECT2-Dependent IGF2BP3

## TL;DR

RBM15 improves 5-fluorouracil effectiveness and reduces gastric cancer progression by altering RNA methylation of ECT2, which affects cancer cell behavior.

## Contribution

Identifies a novel RBM15/IGF2BP3–ECT2 signaling axis regulating EMT and chemosensitivity in gastric cancer via m6A methylation.

## Key findings

- High RBM15 expression correlates with better prognosis in gastric cancer patients.
- RBM15 suppresses cancer cell proliferation, migration, and invasion by modulating ECT2 mRNA methylation.
- RBM15 enhances 5-fluorouracil sensitivity in gastric cancer through ECT2-dependent mechanisms.

## Abstract

Gastric cancer (GC) remains a leading cause of global cancer mortality. Analysis of clinical tissues and multiple cohorts (TCGA, ACRG, Singapore, KUGH) associated high RBM15 expression with favorable prognosis. Functional assays in vitro and in vivo demonstrated that RBM15 suppresses GC cell proliferation, migration, and invasion. Integrated RNA-seq and bioinformatics analyses identified the oncogene ECT2 and the epithelial–mesenchymal transition (EMT) pathway as key downstream effectors of RBM15. Mechanistically, RBM15 regulates the m6A methylation of ECT2 mRNA at the 2,909-base pair site, which modulates its binding to the reader protein IGF2BP3, as confirmed by MeRIP, RIP-qPCR, and RNA pull-down assays. A luciferase reporter assay further validated that this m6A modification regulates ECT2 expression. Furthermore, animal and patient-derived organoid models revealed that RBM15 enhances the sensitivity of GC to 5-fluorouracil (5-FU) chemotherapy in an ECT2-dependent manner. In conclusion, this study defines a novel RBM15/IGF2BP3–ECT2 signaling axis that regulates EMT and chemosensitivity in GC via m6A methylation, providing both mechanistic insights and a potential therapeutic strategy.