Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice.
Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/- mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.
Sakatani
Takashi
T
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kaneda
Atsushi
A
Iacobuzio-Donahue
Christine A
CA
Carter
Mark G
MG
de Boom Witzel
Sten
S
Okano
Hideyuki
H
Ko
Minoru S H
MS
Ohlsson
Rolf
R
Longo
Dan L
DL
Feinberg
Andrew P
AP
D000236:Adenoma / Q000209:etiology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology; D020895:Enterocytes / Q000166:cytology* / Q000378:metabolism; D036387:Ephrin-B1 / Q000032:analysis; D044127:Epigenesis, Genetic; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D016601:RNA-Binding Proteins / Q000032:analysis; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000032:analysis; D051879:Twist-Related Protein 1
D036387:Ephrin-B1; C094335:H19 long non-coding RNA; C491297:MSI1 protein, human; D008840:Microfilament Proteins; C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C026615:villin; D007335:Insulin-Like Growth Factor II