Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice

Takashi Sakatani; Atsushi Kaneda; Christine A. Iacobuzio-Donahue; Mark G. Carter; Sten De Boom Witzel; Hideyuki Okano; Minora S.H. Ko; Rolf Ohlsson; Dan L. Longo; Andrew P. Feinberg

doi:10.1126/science.1108080

Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice

Takashi Sakatani, Atsushi Kaneda, Christine A. Iacobuzio-Donahue, Mark G. Carter, Sten De Boom Witzel, Hideyuki Okano, Minora S.H. Ko, Rolf Ohlsson, Dan L. Longo, Andrew P. Feinberg

School of Medicine

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Abstract

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.

Original language	English (US)
Pages (from-to)	1976-1978
Number of pages	3
Journal	Science
Volume	307
Issue number	5717
DOIs	https://doi.org/10.1126/science.1108080
State	Published - Mar 25 2005

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title = "Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice",

abstract = "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.",

author = "Takashi Sakatani and Atsushi Kaneda and Iacobuzio-Donahue, {Christine A.} and Carter, {Mark G.} and {De Boom Witzel}, Sten and Hideyuki Okano and Ko, {Minora S.H.} and Rolf Ohlsson and Longo, {Dan L.} and Feinberg, {Andrew P.}",

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AU - Sakatani, Takashi

AU - Kaneda, Atsushi

AU - Iacobuzio-Donahue, Christine A.

AU - Carter, Mark G.

AU - De Boom Witzel, Sten

AU - Okano, Hideyuki

AU - Ko, Minora S.H.

AU - Ohlsson, Rolf

AU - Longo, Dan L.

AU - Feinberg, Andrew P.

PY - 2005/3/25

Y1 - 2005/3/25

N2 - 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.

AB - 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.

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Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice

Abstract

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