title: Suppression of intestinal tumorigenesis inApcmutant mice upon Musashi-1 deletion.
abstract: Therapeutic strategies based on a specific oncogenic target are better justified when elimination of that particular oncogene reduces tumorigenesis in a model organism. One such oncogene, Musashi-1 (Msi-1), regulates translation of target mRNAs and is implicated in promoting tumorigenesis in the colon and other tissues. Msi-1 targets include the tumor suppressor adenomatous polyposis coli (Apc), a Wnt pathway antagonist lost in ∼80% of all colorectal cancers. Cell culture experiments have established thatMsi-1is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a mutually repressive feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc and Msi-1 mutually repressive feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, mice with germlineApcmutations (ApcMin) or with theApc1322Ttruncation mutation have a dramatic reduction in intestinal polyp number whenMsi-1is deleted. Taken together, these results provide genetic evidence that Msi-1 contributes to intestinal tumorigenesis driven by Apc loss, and validate the pursuit of Msi-1 inhibitors as chemo-prevention agents to reduce tumor burden.
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Andy R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Ernlund
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: William
authors.initials: W
authors.lastname: McGuinness
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Carl
authors.identifier: 0000-0001-6905-4195
authors.initials: C
authors.lastname: Lehmann
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Kaitlyn
authors.identifier: 0000-0001-6197-4173
authors.initials: K
authors.lastname: Carl
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
authors.forename: Nicole
authors.identifier: 0000-0002-9670-5907
authors.initials: N
authors.lastname: Balmaceda
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA klneuf@ku.edu.
authors.forename: Kristi L
authors.identifier: 0000-0003-3653-9385
authors.initials: KL
authors.lastname: Neufeld
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002452:Cell Count; D049109:Cell Proliferation; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D051880:Receptors, Notch
keywords: Adenomatous polyposis coli; Apc; Intestinal tumorigenesis; Msi-1; Musashi-1; Notch; Wnt