Background: Smad4 and p53 mutations are the most common mutations in human colorectal cancers (CRCs). We evaluated whether and how they are synergistic in intestinal carcinogenesis using novel autochthonous mouse models.
Method: To recapitulate human CRCs, we generated Villin-Cre;Smad4 ;Trp53 mice. We then compared the intestinal phenotype of Villin-Cre;Smad4 ;Trp53 mice (n = 40) with Villin-Cre;Smad4 (n = 30) and Villin-Cre;Trp53 mice (n = 45).
Results: Twenty-week-old Villin-Cre;Smad4 ;Trp53 mice displayed spontaneous highly proliferative intestinal tumors, and 85% of mice developed adenocarcinomas. p21 was downregulated in the intestinal mucosa in Villin-Cre;Smad4 ;Trp53 mice than in Villin-Cre;Smad4 and Villin-Cre;Trp53 mice. Villin-Cre;Smad4 ;Trp53 mice displayed multistep intestinal tumorigenesis and Wnt activation. Long-term CWP232291 (small-molecule Wnt inhibitor) treatment of Villin-Cre;Smad4 ;Trp53 mice suppressed intestinal tumorigenesis and progression. CWP232291 treatment downregulated cancer stem cell (CSC) tumor markers including CD133, Lgr-5, and Sca-1. CWP232291 treatment reduced the CSC frequency. Small-molecule Wnt inhibitors reduced intestinal CSC populations and inhibited their growth, along with Bcl-X downregulation. Furthermore, BH3I-1, a Bcl-X antagonist, increasingly inhibited intestinal CSCs than bulk tumor cells.
Conclusion: Smad4 loss and p53 loss are synergistic in autochthonous intestinal carcinogenesis, by downregulating p21 and activating Wnt/β-catenin pathway.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9089223 | PMC |
| http://dx.doi.org/10.1002/cam4.4533 | DOI Listing |
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