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| Status |
Public on Sep 07, 2023 |
| Title |
BRAFV600E expression in intestinal tissue promotes a cholesterol metabolic gene signature that sustains hyperplasia and characterizes serrated colorectal neoplasia |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
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| Overall design |
20 samples
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| |
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| Contributor(s) |
Rufini A, Farahmand P, Pritchard C, Rzasa P, Sylvius N |
| Citation(s) |
37735514 |
| Submission date |
Jun 07, 2023 |
| Last update date |
Sep 27, 2023 |
| Contact name |
Nicolas Sylvius |
| E-mail(s) |
ns249@le.ac.uk
|
| Organization name |
University of Leicester
|
| Department |
CBS-Genetics
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| Lab |
Genomic Facility
|
| Street address |
University Road
|
| City |
Leicester |
| ZIP/Postal code |
LE1 1ST |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL21810 |
Agilent-074809 SurePrint G3 Mouse GE v2 8x60K Microarray [Feature Number version] |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA981142 |
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