RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33  

作　　者：Cheng-piao Lu Jia-bin Li Dong-bao Li Yu-hong Wang Xiao-gang Jiang Jing-jing Ma Guoqiang Xu 

机构地区：[1]Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences,The Fourth Affiliated Hospital of Soochow University,Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases,Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases,Soochow University,Suzhou,215123,China [2]Department of General Surgery,The First Affiliated Hospital of Soochow University,Suzhou,215006,China [3]Department of Pathology,The First Affiliated Hospital of Soochow University,Suzhou,215006,China [4]Department of Pharmacy,The Fourth Affiliated Hospital of Soochow University,Suzhou Dushu Lake Hospital,Medical Center of Soochow University,Suzhou,215123,China [5]Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,College of Pharmaceutical Sciences,Soochow University,Suzhou,215123,China [6]MOE Key Laboratory of Geriatric Diseases and Immunology,Suzhou Medical College of Soochow University,Suzhou,215123,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1068-1081,共14页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(32171437);the National Key R&D Program of China(2019YFA0802401);the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(22KJB310017);Suzhou Science and Technology Development Project(SZM2023006);Gusu Key Health Talent Program of Suzhou(GSWS2022122);the Young Physician Scientists Program(ML42900323);Interdisciplinary Basic Frontier Innovation Program(YXY2302015)at Suzhou Medical College of Soochow University;the National Center for International Research(2017B01012);the Jiangsu Key Laboratory of Neuropsychiatric Diseases(BM2013003);a project funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions.

摘　　要：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.

关 键 词：RBM39 MRPL33 gastric cancer PROLIFERATION alternative splicing 

分 类 号：R735.2[医药卫生—肿瘤]