V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a.
Linda A. S. Carragher
Kimberley R. Snell
Susan M. Giblett
Victoria S. S. Aldridge
Bipin Patel
S. J. Cook
D. J. Winton
R. Marais
Catrin A. Pritchard
2381/14369
https://figshare.le.ac.uk/articles/journal_contribution/V600EBraf_induces_gastrointestinal_crypt_senescence_and_promotes_tumour_progression_through_enhanced_CpG_methylation_of_p16INK4a_/10110098
The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non-APC mutated CRCs has been defined that have a serrated histopathology and carry the (V600E)BRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing (V600E)Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek-dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β-catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)-dependent, Akt-independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence-associated β-galactosidase and p16(Ink4a). We show that tumour progression is associated with down-regulation of p16(Ink4a) through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify (V600E)BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC-mutated cancers, this subtype arises by the bypassing of a (V600E)Braf driven oncogene-induced senescence programme.
2012-10-24 08:58:07
Aging
Amino Acid Substitution
Animals
Cell Nucleus
Colorectal Neoplasms
Cyclin-Dependent Kinase Inhibitor p16
DNA Methylation
Gastrointestinal Tract
Gene Expression Profiling
Glycogen Synthase Kinase 3
Hyperplasia
Mice
Mutation
Missense
Proto-Oncogene Proteins B-raf
Up-Regulation
beta Catenin