P53 gene mutation increases progastrin dependent colonic proliferation and colon cancer formation in mice |
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Authors: | Ramanathan Vigneshwaran Jin Guangchun Westphalen Christoph Benedikt Whelan Ashley Dubeykovskiy Alexander Takaishi Shigeo Wang Timothy C |
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Affiliation: | Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York 10032, USA. |
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Abstract: | Transgenic mice overexpressing human progastrin (hGAS) show colonic crypt hyper-proliferation and elevated susceptibility to colon carcinogenesis. We aimed to investigate effects of p53 mutation on colon carcinogenesis in hGAS mice. We show that introducing a p53 gene mutation further increases progastrin dependent BrdU labeling and results in markedly elevated number of aberrant crypt foci (ACF) and colonic tumors. We demonstrate that hGAS/Lgr5-GFP mice have higher number of Lgr5+ colonic stem cells per crypt when compared to Lgr5-GFP mice indicating that progastrin changes crypt biology through increased stem cell numbers and additional p53 mutation leads to more aggressive phenotype in this murine colon cancer model. |
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