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- Title
The SF3B1<sup>R625H</sup> mutation promotes prolactinoma tumor progression through aberrant splicing of DLG1.
- Authors
Guo, Jing; Li, Chuzhong; Fang, Qiuyue; Liu, Yulou; Wang, Dawei; Chen, Yiyuan; Xie, Weiyan; Zhang, Yazhuo
- Abstract
Background: Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored. Methods: Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Results: Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Conclusions: Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
- Subjects
CANCER invasiveness; PROLACTINOMA; EPITHELIAL-mesenchymal transition; PI3K/AKT pathway; NUCLEOTIDE sequencing; CELL migration inhibition
- Publication
Journal of Experimental & Clinical Cancer Research (17569966), 2022, Vol 41, Issue 1, p1
- ISSN
1756-9966
- Publication type
Article
- DOI
10.1186/s13046-022-02245-0