Beyond ribosomal function:RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing  

作　　者：Wenkang Fu Yanyan Lin Mingzhen Bai Jia Yao Chongfei Huang Long Gao Ningning Mi Haidong Ma Liang Tian Ping Yue Yong Zhang Jinduo zhang Yanxian Ren Liyun Ding Lunzhi Dai Joseph WLeung Jinqiu Yuan Wenhua Zhang Wenbo Meng 

机构地区：[1]The First School of Clinical Medicne,Lanzhou University,Lanzhou 730030,China [2]Department of General Surgery,the First Hospital of Lanzhou University,Lanzhou 730030,China [3]Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province,the First Hospital of Lanzhou University,Lanzhou 730000,China [4]School of Physical Science and Technology,Lanzhou University,Lanzhou 730000,China [5]National Clinical Research Center for Geriatrics and Department of General Practice,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu 610041,China [6]Division of Gastroenterology,UC Davis Medical Center and Sacramento VA Medical Center,Sacramento,CA 95817,USA [7]Clinical Research Center,Big Data Center,the Seventh Affiliated Hospital,Sun Yat-sen University,Shenzhen 518107,China [8]School of Life Sciences,Lanzhou University,Lanzhou 730000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期3931-3948,共18页药学学报（英文版）

基　　金：the National Key Research and Development Program of China(2022YFC2407405);National Natural Science Foundation of China(82060551,32160230);Natural Science foundation of Gansu Province(22JR5RA891,China);Gansu Provincial Health Industry Research Program(GSWSQH2021-001,China);Science and Technology Bureau Talent Innovation Program of Chengguan District(2019RCCX0038,China).

摘　　要：Cholangiocarcinoma(CCA)is a bile duct malignancy with a dismal prognosis.This study systematically investigated the role of the ribosomal protein S6(RPS6)gene,which is dependent in CCA.We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis.Functional investigations have shown that alterations in RPS6 expression,both gain-and loss-of function could affect the proliferation of CCA cells.In xenograft tumor models,RPS6 overexpression enhances tumorigenicity,whereas RPS6 silencing reduces it.Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle,especially DNA replication.Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6.Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing(AS)events,and combined with RNA immunoprecipitation sequencing,revealed that minichromosome maintenance complex component 7(MCM7)binds to RPS6,which regulates its AS and increases oncogenic activity in CCA.Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer(V-PMO)significantly inhibited the growth of CCA cells,patient-derived organoids,and subcutaneous xenograft tumor.Taken together,the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

关 键 词：CHOLANGIOCARCINOMA Ribosomal protein S6 Alternative splicing p53 Minichromosome maintenance complex component 7 Vivo morpholino Patient-derived organoids 

分 类 号：R735.8[医药卫生—肿瘤]