Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice.
The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine. Here we show that the colonic polyp number is about six times higher in Apc+/Delta716 Cdx2+/- compound mutant mice. Levels of both APC and CDX2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity (LOH) at Apc. In cultured rat intestinal epithelial and human colon cancer cell lines, suppression of CDX2 by antisense RNA caused marked increases in ABI and chromosomal aberrations. This was mediated by stimulation of the mTOR pathway, causing translational deregulation and G1-S acceleration, associated with low levels of p27 and activation of cyclin E-Cdk2. We obtained similar results in the colonic mucosa of Apc+/Delta716) Cdx2+/- compound mutant mice. Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells. High ABI in all cell lines was suppressed by mTOR inhibitors LY294002 and rapamycin. These results suggest that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability.
Aoki
Koji
K
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Tamai
Yoshitaka
Y
Horiike
Shigeo
S
Oshima
Masanobu
M
Taketo
Makoto M
MM
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000705:Anaphase; D000818:Animals; D001973:Bromodeoxyuridine; D000071616:CDX2 Transcription Factor; D002470:Cell Survival; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D016193:G1 Phase; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016372:RNA, Antisense / Q000494:pharmacology; D051381:Rats; D016196:S Phase; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators
D025601:Adenomatous Polyposis Coli Protein; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; D015534:Trans-Activators; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D001973:Bromodeoxyuridine