P53 Gene Mutation Increases Progastrin Dependent Colonic Proliferation and Colon Cancer Formation in Mice

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.

Keywords: :

• Progastrin
• p53
• Colon cancer
• Azoxymethane
• Lgr5

ACKNOWLEDGMENTS

We would like to express our gratitude to Prof. Arthur Shulkes (Department of Surgery, University of Melbourne, Austin campus, Heidelberg, Victoria, Australia) for performing the mice serum progastrin radioimmunoassay. This work was supported by the NIH through a grant (No. 5 R01 DK052778) to Timothy C. Wang.