Bibliographic Details
| Title: |
Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing |
| Authors: |
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 W. Leung, Jinqiu Yuan, Wenhua Zhang, Wenbo Meng |
| Source: |
Acta Pharmaceutica Sinica B, Vol 14, Iss 9, Pp 3931-3948 (2024) |
| Publisher Information: |
Elsevier, 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Therapeutics. Pharmacology |
| Subject Terms: |
Cholangiocarcinoma, Ribosomal protein S6, Alternative splicing, p53, Minichromosome maintenance complex component 7, Vivo morpholino, Therapeutics. Pharmacology, RM1-950 |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2211-3835 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2211383524002582; https://doaj.org/toc/2211-3835 |
| DOI: |
10.1016/j.apsb.2024.06.028 |
| Access URL: |
https://doaj.org/article/14fb145ecfbb4eaf95fc86109a774fc8 |
| Accession Number: |
edsdoj.14fb145ecfbb4eaf95fc86109a774fc8 |
| Database: |
Directory of Open Access Journals |
