Gastric cancer is a malignant gastrointestinal disease characterized by high morbidity and mortality rates worldwide. The occurrence and progression of gastric cancer are influenced by various factors, including the abnormal alternative splicing of key genes. Recently, RBM39 has emerged as a tumor biomarker that regulates alternative splicing in several types of cancer. However, the specific functions and key alternative splicing events modulated by RBM39 in gastric cancer are still unclear. In this work, bioinformatic analysis of The Cancer Genome Atlas (TCGA) database and immunoblotting of patient tissue samples revealed that RBM39 was highly expressed in gastric cancer tissues and that its elevated expression significantly reduced overall patient survival. Cell-line-based and tumor xenograft experiments demonstrated that RBM39 knockdown attenuated the growth of gastric cancer cells both in vitro and in vivo. Mechanistically, through RNA-seq, minigene, and RT‒PCR, we discovered and further validated that RBM39 inhibited exon 3 skipping, thereby modulating the splicing of MRPL33. The long isoform MRPL33-L, which includes exon 3, but not the short isoform MRPL33-S, which lacks exon 3, significantly promoted the proliferation and colony formation of gastric cancer cells. Furthermore, we observed an increased percent-splice-in (PSI) of MRPL33 in gastric cancer tissues. Genetic manipulation and pharmacological treatment with the RBM39 degrader indisulam demonstrated that RBM39 regulated cell proliferation by influencing the splicing switch of MRPL33 in gastric cancer cells and a xenograft mouse model. Our findings indicate that RBM39 regulates the oncogenic splicing of MRPL33 and suggest that it may serve as a potential therapeutic target for gastric cancer.
Keywords: MRPL33; RBM39; alternative splicing; gastric cancer; proliferation.
© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.