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Published on: October 6, 2014
Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion
Andy R Wolfe1, Amanda Ernlund1, William McGuinness1
1Department of Molecular Biosciences, University of Kansas, 7049 Haworth Hall, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.
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 (Apc ) 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.
Insights
Deleting Musashi-1 (Msi-1) suppresses intestinal tumors driven by Apc loss. This genetic evidence supports Msi-1 inhibitors as potential chemo-prevention agents for reducing tumor burden.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Musashi-1 (Msi-1) is an oncogene implicated in tumorigenesis by regulating mRNA translation.
- Msi-1 targets adenomatous polyposis coli (Apc), a tumor suppressor crucial in colorectal cancer.
- Msi-1 and Apc form a mutually repressive feedback loop, with Msi-1 being a Wnt target.
Purpose of the Study:
- To investigate the role of Msi-1 in intestinal tumorigenesis driven by Apc loss.
- To determine if Msi-1 deletion suppresses tumor development in a mouse model.
- To validate Msi-1 as a therapeutic target for colorectal cancer prevention.
Main Methods:
- Generation and analysis of Msi-1 knockout mice with Apc mutations.
- Assessment of intestinal phenotypes, including Wnt and Notch signaling, proliferation, and stem cell populations.
- Evaluation of polyp formation in mice lacking Msi-1 and carrying Apc mutations.
Main Results:
- Mice lacking Msi-1 exhibited altered Apc-Msi-1 feedback, reduced Wnt/Notch signaling, and decreased proliferation.
- Deletion of Msi-1 significantly reduced intestinal polyp number in mice with Apc mutations.
- These findings demonstrate Msi-1's contribution to Apc-loss-driven intestinal tumorigenesis.
Conclusions:
- Msi-1 plays a critical role in promoting intestinal tumorigenesis associated with Apc loss.
- Targeting Msi-1 with inhibitors could be a viable strategy for chemo-prevention in colorectal cancer.
- Genetic validation of Msi-1 as a therapeutic target offers a new avenue for cancer treatment.
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