Study summary · research use only
An unexpected tumor-resistant phenotype from floxing PAK1 in a mouse model of colitis associated cancer
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined PAK1 in a model of colitis-associated cancer, comparing total PAK1 knockout (PAK1KO), floxed PAK1 controls (PAK1fl), and intestinal-epithelium-specific conditional knockout (PAK1CKO) mice made by crossing Pak1-floxed with VillinCre mice. Unexpectedly, inflammation and tumorigenesis were greatly reduced in PAK1fl mice compared with wild-type or PAK1KO mice after AOM/DSS treatment; PAK1CKO mice had higher tumor incidence and counts than PAK1fl but still lower than PAK1KO or wild-type. Crossed with IL10-knockout mice, PAK1CKO was associated with an exacerbated hyperproliferative phenotype and earlier morbidity. Despite normal Pak1 mRNA in PAK1fl colonic tissue, PAK1 protein was higher than wild-type on immunohistochemistry, and both PAK1fl and PAK1CKO mice resisted microbiome shifts more than PAK1KO or wild-type; the authors suggest floxing itself may have altered Pak1 expression.
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.
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