癌症研究
RNA剪接
选择性拼接
生物
胰腺癌
分子生物学
基因
细胞生物学
基因亚型
核糖核酸
癌症
遗传学
作者
Amina Jbara,Kuan-Ting Lin,Chani Stossel,Zahava Siegfried,Haya Shqerat,Adi Amar-Schwartz,Ela Elyada,Maxim Mogilevsky,Maria Raitses‐Gurevich,Jared L. Johnson,Tomer M. Yaron,Ofek Ovadia,Gun Ho Jang,Miri Danan-Gotthold,Lewis C. Cantley,Erez Y. Levanon,Steven Gallinger,Adrian R. Krainer,Talia Golan,Rotem Karni
出处
期刊:Nature
[Springer Nature]
日期:2023-03-22
卷期号:617 (7959): 147-153
被引量:23
标识
DOI:10.1038/s41586-023-05820-3
摘要
Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases 1–3 . Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.
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