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

引用

ACTA PHARMACEUTICA SINICA B 2024年第9期14卷 3931-3948页

作者： Fu, Wenkang Lin, Yanyan Bai, Mingzhen Yao, Jia Huang, Chongfei Gao, Long Mi, Ningning Ma, Haidong Tian, Liang Yue, Ping Zhang, Yong Zhang, Jinduo Ren, Yanxian Ding, Liyun Dai, Lunzhi Leung, Joseph W. Yuan, Jinqiu Zhang, Wenhua Meng, Wenbo Lanzhou Univ Sch Clin Med 1 Lanzhou 730030 Peoples R China Lanzhou Univ Hosp 1 Key Lab Biotherapy & Regenerat Med Gansu Prov Lanzhou 730000 Gansu Peoples R China Lanzhou Univ Hosp 1 Dept Gen Surg Lanzhou 730030 Peoples R China Lanzhou Univ Sch Phys Sci & Technol Lanzhou 730000 Peoples R China Sichuan Univ West China Hosp Natl Clin Res Ctr Geriatr Chengdu 610041 Peoples R China Sichuan Univ West China Hosp Dept Gen Practice State Key Lab Biotherapy Chengdu 610041 Peoples R China UC Davis Med Ctr Div Gastroenterol Sacramento CA 95817 USA Sacramento VA Med Ctr Sacramento CA 95817 USA Sun Yat Sen Univ Affiliated Hosp 7 Clin Res Ctr Big Data Ctr Shenzhen 518107 Guangdong Peoples R China Lanzhou Univ Sch Life Sci Lanzhou 730000 Peoples R China

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 PROTEIN S6 PHOSPHORYLATION PRE-MESSENGER-RNA EXPRESSION CANCER BINDING BIOGENESIS ACTIVATION GENERATION IMPAIRMENT THERAPIES

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