Period 2 mutation accelerates ApcMin/+ tumorigenesis.

Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 ( Per2 ) is a key circadian clock gene. Per2 mutant ( Per2 m/m ) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc Min/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2 m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. Apc Min/+ Per2 m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc Min/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. (Mol Cancer Res 2008;6(11):1786–93)