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U2AF1 S34F enhances tumorigenic potential of lung cells by exhibiting synergy with KRAS mutation and altering response to environmental stress.
- Source :
-
BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 15. Date of Electronic Publication: 2024 Sep 15. - Publication Year :
- 2024
-
Abstract
- Although U2AF1 <superscript> S34F </superscript> is a recurrent splicing factor mutation in lung adenocarcinoma (ADC), U2AF1 <superscript> S34F </superscript> alone is insufficient for producing tumors in previous models. Because lung ADCs with U2AF1 <superscript> S34F </superscript> frequently have co-occurring KRAS mutations and smoking histories, we hypothesized that tumor-forming potential arises from U2AF1 <superscript> S34F </superscript> interacting with oncogenic KRAS and environmental stress. To elucidate the effect of U2AF1 <superscript> S34F </superscript> co-occurring with a second mutation, we generated human bronchial epithelial cells (HBEC3kt) with co-occurring U2AF1 <superscript> S34F </superscript> and KRAS <superscript> G12V </superscript> . Transcriptome analysis revealed that co-occurring U2AF1 <superscript> S34F </superscript> and KRAS <superscript> G12V </superscript> differentially impacts inflammatory, cell cycle, and KRAS pathways. Subsequent phenotyping found associated suppressed cytokine production, increased proliferation, anchorage-independent growth, and tumors in mouse xenografts. Interestingly, HBEC3kts harboring only U2AF1 <superscript> S34F </superscript> display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1 <superscript> S34F </superscript> may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRAS <superscript> G12V </superscript> , which synergize with U2AF1 <superscript> S34F </superscript> to transform the cell.
Details
- Language :
- English
- ISSN :
- 2692-8205
- Database :
- MEDLINE
- Journal :
- BioRxiv : the preprint server for biology
- Publication Type :
- Academic Journal
- Accession number :
- 39314447
- Full Text :
- https://doi.org/10.1101/2024.09.11.612492