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In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
Cited1 deficiency suppresses intestinal tumorigenesis
Valérie Méniel1, Fei Song, Toby Phesse
1School of Biological Sciences, Cardiff University, Cardiff, Wales, UK.
Plos Genetics
|August 13, 2013
Summary
Cited1 deficiency reduces intestinal tumors in mice by restraining Wnt signaling. However, it initially exacerbates Apc deletion phenotypes, highlighting Cited1
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Apc deletion in the intestine alters crypt-villus architecture and gene expression, including upregulation of Cited1.
- The role of Cited1 in colorectal carcinogenesis is currently unknown.
- Cited1 is upregulated in both human and murine tumors.
Purpose of the Study:
- To investigate the role of Cited1 in intestinal tumorigenesis.
- To determine the impact of Cited1 deficiency on tumor growth, initiation, and associated molecular pathways.
- To elucidate the mechanism by which Cited1 influences Wnt signaling in the context of Apc mutations.
Main Methods:
- Crossing Cited1 null mice with Apc(Min/+) and AhCre(+)Apc(fl/fl) models.
- Assessing tumor multiplicity, cell proliferation, and apoptosis.
- Performing transcriptome analysis to identify pathway alterations.
Main Results:
- Constitutive Cited1 deficiency increased survival in Apc(Min/+) mice (230.5 to 515 days).
- Cited1 deficiency paradoxically accentuated immediate post-Apc deletion phenotypes, including increased cell death and differentiation defects.
- Transcriptome analysis revealed pathway changes in p53, PI3K, and Wnt signaling, with Cited1 deficiency leading to Wnt pathway hyper-activation via β-catenin.
- Cited1 deficiency decreased intestinal tumorigenesis in Apc(Min/+) mice, suggesting a tumor-repressive role.
Conclusions:
- Cited1 restrains Wnt pathway activity at the β-catenin level immediately following Apc deletion.
- Cited1 deficiency leads to Wnt pathway hyper-activation, causing an exaggerated Wnt phenotype with elevated cell death.
- Cited1 deficiency decreases intestinal tumorigenesis, indicating a role in constraining Wnt activity for optimal adenoma formation and maintenance.
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