Loss of Imprinting of Igf2 Alters Intestinal Maturation and Tumorigenesis in Mice

• Published in: Science (American Association for the Advancement of Science) 2005-03, Vol.307 (5717), p.1976-1978
• Main Authors: Sakatani, Takashi, Kaneda, Atsushi, Iacobuzio-Donahue, Christine A, Carter, Mark G, de Boom Witzel, Sten, Okano, Hideyuki, Ko, Minoru S. H, Ohlsson, Rolf, Longo, Dan L, Feinberg, Andrew P
• Format: Article
• Language: English
• Subjects: Adenoma; Adenoma - etiology; Adenoma - pathology; Animal tumors. Experimental tumors; Animals; Apoptosis; Biological and medical sciences; Cancer; Care and treatment; Cell Differentiation; Cell nucleus; Cell Proliferation; Cellular differentiation; Cellular immunity; Colon - cytology; Colon - metabolism; Colonic Neoplasms - etiology; Colonic Neoplasms - pathology; Colorectal cancer; Crypts; Enterocytes - cytology; Enterocytes - metabolism; Ephrin-B1 - analysis; Epigenesis, Genetic; Epithelial cells; Epithelium; Experimental digestive system and abdominal tumors; Female; Genes; Genomes; Genomic Imprinting; Humans; Individualized Instruction; Insulin; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Intestinal crypts; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Intestinal Neoplasms - etiology; Intestinal Neoplasms - pathology; Intestines - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microfilament Proteins - analysis; Mucosa; Nerve Tissue Proteins - analysis; Nuclear Proteins - analysis; Pathology; Proteins; RNA, Long Noncoding; RNA, Untranslated - genetics; RNA-Binding Proteins - analysis; Rodents; Scientific Concepts; Stem cells; Stem Cells - cytology; Transcription Factors - analysis; Tumors; Tumours; Twist-Related Protein 1
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1108080

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[superscript +/-] mice with male Apc[superscript +/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.