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Updated: Sep 12, 2025
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
An unexpected tumor-resistant phenotype from floxing PAK1 in a mouse model of colitis associated cancer
Kristine Jimenez1, Lambert Lindeck-Pozza1, Adrian P Frick1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
Abstract:
Inflammatory bowel disease (IBD) and colitis-associated cancer are associated with activation of PAK1 (p-21 activated kinase 1). We previously found that total knockout of PAK1 (PAK1KO) reduced tumorigenesis upon AOM/DSS but enhanced tumorigenesis in another model of IBD with total knockout of IL10 (IL10KO). To better understand the specific role of epithelial PAK1, we crossed Pak1 floxed (PAK1fl) with VillinCre mice for a conditional knockout of PAK1 in intestinal epithelia (PAK1CKO). PAK1fl were included as additional controls. Unexpectedly, inflammation and tumorigenesis were greatly reduced in PAK1fl compared to WT or PAK1KO after AOM/DSS treatment. PAK1CKO had higher tumor incidence and counts compared to PAK1fl, but was still lower in comparison to PAK1KO or WT. When crossed with IL10KO mice, PAK1CKO exacerbated the expected hyperproliferative phenotype, resulting in early mouse morbidity. Despite normal Pak1 mRNA expression in PAK1fl colonic lysates, PAK1 protein expression on immunohistochemistry was higher that WT. Both PAK1fl and PAK1CKO mice were more resistant to shifts in microbiome, and remained clustered together compared to WT or PAK1KO. Altogether, our results suggest that floxing itself may have altered Pak1 expression, which conferred protection from AOM/DSS carcinogenesis.
Insights
The floxing process, not epithelial p-21 activated kinase 1 (PAK1) deletion, unexpectedly reduced inflammation and tumorigenesis in mice. This suggests altered PAK1 expression from floxing confers protection against colitis-associated cancer.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Inflammatory bowel disease (IBD) and colitis-associated cancer involve p-21 activated kinase 1 (PAK1) activation.
- Previous studies showed conflicting roles for total PAK1 knockout (PAK1KO) in IBD and cancer models.
Purpose of the Study:
- To investigate the specific role of epithelial PAK1 in IBD and colitis-associated cancer.
- To understand how conditional knockout of PAK1 in intestinal epithelia (PAK1CKO) affects these conditions.
Main Methods:
- Generated PAK1CKO mice by crossing Pak1 floxed (PAK1fl) with VillinCre mice.
- Administered AOM/DSS treatment to PAK1fl, PAK1CKO, WT, and PAK1KO mice.
- Analyzed inflammation, tumorigenesis, Pak1 expression (mRNA and protein), and microbiome shifts.
Main Results:
- PAK1fl mice showed significantly reduced inflammation and tumorigenesis after AOM/DSS compared to WT.
- PAK1CKO mice had increased tumor incidence compared to PAK1fl but less than WT or PAK1KO.
- PAK1CKO exacerbated hyperproliferation in IL10KO mice, leading to morbidity.
- Floxing itself (PAK1fl) appeared to confer protection, possibly due to altered PAK1 protein levels and microbiome resistance.
Conclusions:
- Epithelial PAK1 plays a complex role in IBD and colitis-associated cancer.
- The floxing procedure itself may induce protective effects against carcinogenesis, independent of targeted gene deletion.
- Further research is needed to elucidate the mechanisms behind floxing-induced protection and PAK1's multifaceted role.
