The cyclin-dependent kinase inhibitor p27Kip1 is a negative regulator of the cell cycle. Reduced expression of p27Kip1 has prognostic significance in several human epithelial cancers. Loss of p27Kip1 expression in cancer cells correlates with tumor aggressiveness, depth of tumor cell invasion and with lack of tumor cell differentiation. However, p27Kip1 also promotes apoptosis and contraction of effector CD4+ T cells, suggesting the potential that suppression of epithelial tumorigenesis may be linked to an intrinsic function of p27Kip1 in T cells. Here we show both mRNA and protein expression of p27Kip1 are significantly decreased in a murine model wherein a T cell-restricted deletion of the gene encoding the TGF-β intermediate, Smad4 (Smad4TKO), results in spontaneous colitis that invariably progresses to colon cancer by the age of 8 months. This phenotype is associated with a consistent decline in the mucosal expression of p27Kip1. To further investigate the role of p27Kip1 in the maintenance of intestinal mucosal homeostasis, we generated a ‘double knockout’ (Smad4TKO / p27Kip1-/- or ‘DKO’) mouse model in which a germ line p27Kip1 gene deletion (p27Kip1-/-) is combined with the T cell-restricted deletion of the Smad4 gene (Smad4TKO). All DKO mice develop spontaneous gastrointestinal inflammation and colon carcinoma by 1-2 months and 3 months of age, respectively. The p27Kip1 gene deletion, when combined with the T cell-restricted deletion of the Smad4 gene, leads to progressive inflammatory cytokine production (TNF-α, IFN-γ, iNOS, IL-6, IL-1β), activation of Stat1 and Stat3 and suppression of the expression of the tumor suppressor, 15-PGDH. Collectively our data suggest that p27Kip1 deficiency promotes gastrointestinal epithelial malignancy through both enhancement of proliferation of mucosal epithelial cells and through expansion of mucosal effector memory T cells.
Citation Format: Sung Hee Choi, Byung-Gyu Kim, Letterio J. John. p27Kip1 suppression of colitis-associated colon cancer mediated through cell intrinsic function in both mucosal epithelia and mucosal T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-251. doi:10.1158/1538-7445.AM2014-LB-251