Role of c-Myc in intestinal tumorigenesis of the Apc min/+ mouse1

• Published in: Cancer biology & therapy Vol. 5; no. 12; pp. 1658 - 1664
• Main Authors: Ignatenko, Natalia A, Holubec, Hana, Besselsen, David G, Blohm-Mangone, Karen A, Padilla-Torres, Jose, Nagle, Raymond B., de Alboranc, Ignacio Moreno, Guillen-R, Jose M, Gerner, Eugene W
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 31-12-2006
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cycle; Landes; Organogenesis; Proteins
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.5.12.3376

The c-MYC oncogene plays an important role in tumorigenesis and is commonly highly expressed in gastrointestinal cancers. In colon cells, c-MYC is regulated by the adenomatous polyposis coli (Apc) tumor suppressor gene. Multiple intestinal neoplasia (ApcMin/+ or Min) mice are heterozygous for a truncating Apc mutation and serve as a model of familial adenomatous polyposis (FAP) disease. To study the role of c-Myc in the mutant Apc-mediated colon tumorigenesis, we have developed a transgenic mouse with the conditional deletion of the floxed c-Myc alleles in the intestinal crypts of ApcMin/+ mice (ApcMin/+; c-Mycfl/fl). The floxed c-Myc deletion was initiated via a Cre recombinase controlled by the intestine-specific transcriptional regulatory elements of the liver fatty acid-binding protein gene (Fabpl4×at-132). Fabpl4×at-132-mediated Cre expression and recombination resulted in a two-fold decrease in c-MYC protein expression with no effect on intestinal tract morphology. Small intestinal tumorigenesis was significantly suppressed throughout the small intestinal tract of ApcMin/+; c-Mycfl/fl mice compared to c-Myc wild type littermates. In ApcMin/+; c-Mycfl/fl mice, the intestinal apoptosis was higher in the areas of the small intestine with the decreased c-Myc protein expression (P= 0.0016, compared to their littermates with the wild type c-Myc). Thus, conditional inactivation of c-Myc, mediated by Fabpl4×at-132-driven Cre-recombinase, suppresses Apc-dependent intestinal tumorigenesis in adult ApcMin/+) mice, without apparent effect on normal intestinal mucosa.