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.
The authors declare no competing or financial interests.
Conceived and designed the experiments: A.R.W., A.E., K.L.N. Performed the experiments: A.R.W., A.E., C.L., K.C., N.B., W.M. Analyzed the data: A.R.W., A.E., K.L.N. Prepared the article: A.R.W., K.L.N.
This work was supported by J.R. and Inez Jay fund of the Higuchi Biosciences Center, a University of Kansas General Research Fund, the Kansas Masonic Foundation Pilot Research Program of the KU Cancer Center (P30CA168524), the University of Kansas Research Investment Council, the National Cancer Institute (R01CA178831 to K.L.N.) and an IDeA award from the National Institute of General Medical Sciences (P20 GM103418). Deposited in PMC for release after 12 months.
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.197574.supplemental
- Received September 20, 2016.
- Accepted January 5, 2017.
- © 2017. Published by The Company of Biologists Ltd