Wnt-driven intestinal tumourigenesis is suppressed by Chk1 deficiency but enhanced by conditional haploinsufficiency

• Published in: Oncogene Vol. 33; no. 31; pp. 4089 - 4096
• Main Authors: Greenow, K R, Clarke, A R, Williams, G T, Jones, R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 31.07.2014
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Animals; Apoptosis; Cancer; Carcinogenesis; Cell cycle; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Checkpoint Kinase 1; CHK1 protein; Colorectal cancer; Colorectal carcinoma; Development and progression; Disease Progression; DNA Damage; Genetic aspects; Genetic research; Genomics; Haploinsufficiency; Intestine, Small - metabolism; Intestine, Small - pathology; Mice; Oncology, Experimental; Protein Kinases - genetics; Protein Kinases - metabolism; Small intestine; Tumorigenesis; Tumors; Wnt protein; Wnt Proteins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.371

Chk1 is essential in maintaining genomic stability due to its role in cell cycle regulation. Several recent studies have indicated that the abrogation of checkpoints in tumourigenesis through the inhibition of Chk1 may be of therapeutic value. To further investigate the role of Chk1 in the mouse small intestine and its potential role as a therapy for colorectal cancer, we simultaneously deleted Chk1 and Apc in the mouse small intestine. We found that homozygous loss of Chk1 is not compatible with Wnt-driven proliferation and resulted in the suppression of Wnt-driven tumourigenesis in the mouse small intestine. In contrast, heterozygous loss of Chk1 in a Wnt-driven background resulted in an increase in DNA damage and apoptosis and accelerated both tumour development and progression.