Open AccessSuppression of intestinal tumorigenesis in Apc mutant mice by Musashi-1 deletion
Author(s) -
Andy Wolfe,
Amanda Ernlund,
William McGuinness,
Carl P. Lehmann,
Kaitlyn Carl,
Nicole Balmaceda,
Kristi L. Neufeld
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.197574
Subject(s) - biology , wnt signaling pathway , carcinogenesis , adenomatous polyposis coli , cancer research , oncogene , germline , suppressor , beta catenin , mutation , familial adenomatous polyposis , germline mutation , cell , genetics , cancer , colorectal cancer , signal transduction , cell cycle , gene
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 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 that Msi-1 is a Wnt target, thus positioning Msi-1 and Apc as mutual antagonists in a double negative feedback loop. Here, we report that intestines from mice lacking Msi-1 display aberrant Apc/Msi-1 double negative feedback, reduced Wnt and Notch signaling, decreased proliferation, and changes in stem cell populations, features predicted to suppress tumorigenesis. Indeed, ApcMin and Apc1322T mice have a dramatic reduction in intestinal polyp number when Msi-1 is deleted. 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.