RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability

RNA-binding proteins (RBPs) critically regulate post-transcriptional gene expression, yet their roles in chemotherapy resistance remain underexplored. Here, through a targeted siRNA screen of 40 RBM family members, we identified RNA-binding motif protein 8 A (RBM8A) as central orchestrator of oxaliplatin-induced DNA damage in gastric cancer (GC). Functional studies demonstrated that RBM8A promotes tumor proliferation and chemoresistance by recruiting the RNA helicase eIF4A3 to stabilize epidermal growth factor receptor (EGFR) mRNA, shielding it from exonucleolytic degradation. This stabilization sustains EGFR protein levels, enabling nuclear EGFR-DNA-PKcs complex formation to drive non-homologous end joining (NHEJ)-mediated DNA repair and suppress oxaliplatin-induced apoptosis. Therapeutic targeting of this axis with the EGFR inhibitor gefitinib restored oxaliplatin sensitivity in vitro and synergistically suppressed RBM8A-driven xenograft growth in vivo. Additionally, single-cell RNA-seq revealed RBM8A enrichment in malignant gastric epithelial cells, while tissue microarrays confirmed that dual RBM8A/EGFR overexpression predicts the poorest survival outcomes. Collectively, our findings define the RBM8A-eIF4A3-EGFR axis as a druggable determinant of chemoresistance and establish RBM8A as both a prognostic biomarker and therapeutic target in GC.

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Publication Details

Journal
Oncogene
Published
2025-12-07
DOI
https://doi.org/10.1038/s41388-025-03655-y
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.00
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article

RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability

Qiong Yan, Guangtao Gao, Siyue Mao, Fangmei An et al.
Oncogene
RNA Research and Splicing
article

RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability

Qiong Yan, Guangtao Gao, Siyue Mao, Fangmei An, Jinchen Li, Haiyan Wu, Yani Pan, Tao Hong, Zhangding Wang, Mei Yang, Ying Xiang, Liyang Su, Wenjun Li, Nannan Zhang, Yuxiang Ma, Yanmei Zhu, Yue Tao, Xin Fu, Ping Jiang, Guifang Xu, Yinya Pan
article en

Abstract

RNA-binding proteins (RBPs) critically regulate post-transcriptional gene expression, yet their roles in chemotherapy resistance remain underexplored. Here, through a targeted siRNA screen of 40 RBM family members, we identified RNA-binding motif protein 8 A (RBM8A) as central orchestrator of oxaliplatin-induced DNA damage in gastric cancer (GC). Functional studies demonstrated that RBM8A promotes tumor proliferation and chemoresistance by recruiting the RNA helicase eIF4A3 to stabilize epidermal growth factor receptor (EGFR) mRNA, shielding it from exonucleolytic degradation. This stabilization sustains EGFR protein levels, enabling nuclear EGFR-DNA-PKcs complex formation to drive non-homologous end joining (NHEJ)-mediated DNA repair and suppress oxaliplatin-induced apoptosis. Therapeutic targeting of this axis with the EGFR inhibitor gefitinib restored oxaliplatin sensitivity in vitro and synergistically suppressed RBM8A-driven xenograft growth in vivo. Additionally, single-cell RNA-seq revealed RBM8A enrichment in malignant gastric epithelial cells, while tissue microarrays confirmed that dual RBM8A/EGFR overexpression predicts the poorest survival outcomes. Collectively, our findings define the RBM8A-eIF4A3-EGFR axis as a druggable determinant of chemoresistance and establish RBM8A as both a prognostic biomarker and therapeutic target in GC.

OncogeneVol. 45(2)
Nanjing University of Chinese Medicine (CN), Anhui Medical University (CN), Nantong University (CN), Nanjing Drum Tower Hospital (CN), The Affiliated Taizhou People's Hospital of Nanjing Medical University (CN), First Affiliated Hospital of Anhui Medical University (CN), Wuxi People's Hospital (CN), YangPu Geriatric Hospital (CN), Yangpu Hospital of Tongji University (CN), Taizhou University (CN)
Openalex Percentile: Top 64%
RNA Research and Splicing
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