RRC ID 47446
Author Wolfe AR, Ernlund A, McGuinness W, Lehmann C, Carl K, Balmaceda N, Neufeld KL.
Title Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion.
Journal J Cell Sci
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.
Volume 130(4)
Pages 805-813
Published 2017-2-15
DOI 10.1242/jcs.197574
PII jcs.197574
PMID 28082422
PMC PMC5339888
MeSH Adenomatous Polyposis Coli / genetics* Animals Carcinogenesis / metabolism* Carcinogenesis / pathology* Cell Count Cell Proliferation Colonic Polyps / metabolism Colonic Polyps / pathology Disease Models, Animal Epithelium / metabolism Epithelium / pathology Gene Deletion* Intestinal Neoplasms / metabolism* Intestinal Neoplasms / pathology* Intestine, Small / metabolism Intestine, Small / pathology Mice Mice, Mutant Strains Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / metabolism RNA-Binding Proteins / genetics* RNA-Binding Proteins / metabolism Receptors, Notch / metabolism Stem Cells / metabolism Wnt Signaling Pathway
IF 4.573
Times Cited 4
Mice RBRC04435