hnRNPU-mediated pathogenic alternative splicing drives gastric cancer progression.

Abstract

Background: Alternative splicing (AS) is a process that facilitates the differential inclusion of exonic sequences from precursor messenger RNAs, significantly enhancing the diversity of the transcriptome and proteome. In cancer, pathogenic AS events are closely related to cancer progression. This study aims to investigate the role and regulatory mechanisms of AS in gastric cancer (GC).

Methods: We analyzed AS events in various tumor samples and identified hnRNPU as a key splicing factor in GC. The effects of hnRNPU on cancer progression were assessed through in vitro and in vivo experiments. Gene knockout models and the FTO inhibitor (meclofenamic acid) were used to validate the interaction between hnRNPU and FTO and their impact on AS.

Results: We found that hnRNPU serves as a key splicing factor in GC, and its high expression is associated with poor clinical prognosis. Genetic depletion of hnRNPU significantly reduced GC progression. Mechanistically, the m⁶A demethylase FTO interacts with hnRNPU transcripts, decreasing the m⁶A modification levels of hnRNPU, which leads to exon 14 skipping of the MET gene, thereby promoting GC progression. The FTO inhibitor meclofenamic acid effectively inhibited GC cell growth both in vitro and in vivo.

Conclusion: The FTO/hnRNPU axis induces aberrant exon skipping of MET, thereby promoting GC cell growth. Targeting the FTO/hnRNPU axis may interfere with abnormal AS events and provide a potential diagnostic and therapeutic strategy for GC.