# Landscape of splicing factors in early-onset gastric cancer reveals SRSF1 as a key driver of oxaliplatin resistance

## TL;DR

This study explores how splicing factors influence early-onset gastric cancer, identifying SRSF1 as a key driver of resistance to the chemotherapy drug oxaliplatin.

## Contribution

The study identifies SRSF1 as a novel driver of oxaliplatin resistance in early-onset gastric cancer through splicing regulation.

## Key findings

- Most splicing factors are upregulated in early-onset gastric cancer with low somatic mutation rates.
- Three distinct splicing regulatory patterns are associated with immune function, tumor mutational burden, and chemotherapy response.
- SRSF1 overexpression promotes oxaliplatin resistance, colony formation, and exon skipping in tumor-related genes.

## Abstract

The incidence of early-onset gastric cancer (EOGC) is increasing. While RNA alternative splicing critically regulates cancer progression, and abnormal changes in splicing factors (SFs) can affect alternative splicing regulation, their roles in EOGC remain unclear. Using multi-omics approaches, we explored the expression and regulatory patterns of 75 SFs in EOGC and further analyzed the differences associated with different regulatory patterns. We investigated the role of serine/arginine-rich splicing factor 1 (SRSF1) in regulating oxaliplatin (OXA) resistance and malignant phenotypes in EOGC. The results showed that the expression levels of most SFs in the EOGC samples were significantly upregulated, while the somatic mutation rate of SFs was low. Based on the expression of SFs, the EOGC population can be stably divided into three splicing regulatory patterns, which differ in immune function, tumor mutational burden, and the anticipated response to chemotherapy drugs. Overexpressing SRSF1 confers OXA resistance to EOGC cells, promotes colony formation, and inhibits apoptosis, and it could promote exon skipping in downstream genes, thereby altering tumor-related functions. This study reveals the expression landscape of SFs in EOGC and highlights the disparities in biological functions across various splicing regulatory patterns. SRSF1 could be a potential therapeutic target and biomarker for overcoming OXA resistance in EOGC.