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RETRACTED ARTICLE

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J Cell Sci. 2017 Feb 15;130(4):805-813. doi: 10.1242/jcs.197574. Epub 2017 Jan 12.

Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion.

Author information

1
Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
2
Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA klneuf@ku.edu.

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 that Msi-1 is 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 germline Apc mutations (ApcMin ) or with the Apc1322T truncation mutation have a dramatic reduction in intestinal polyp number when Msi-1 is 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.

KEYWORDS:

Adenomatous polyposis coli; Apc; Intestinal tumorigenesis; Msi-1; Musashi-1; Notch; Wnt

PMID:
28082422
PMCID:
PMC5339888
DOI:
10.1242/jcs.197574
[Indexed for MEDLINE]
Free PMC Article

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