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 beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-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 beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-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 beta-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 beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.
Wood
Patricia A
PA
Medical Chronobiology Laboratory, Dorn Research Institute, Columbia, South Carolina, USA. patricia.wood2@va.gov
Yang
Xiaoming
X
Taber
Andrew
A
Oh
Eun-Young
EY
Ansell
Christine
C
Ayers
Stacy E
SE
Al-Assaad
Ziad
Z
Carnevale
Kevin
K
Berger
Franklin G
FG
Peña
Maria Marjorette O
MM
Hrushesky
William J M
WJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002940:Circadian Rhythm; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D003111:Colonic Polyps / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D017491:Genes, APC; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D007417:Intestinal Polyps / Q000473:pathology; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D056950:Period Circadian Proteins; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D051176:beta Catenin