Haploinsufficiency of Casitas B-Lineage Lymphoma Augments the Progression of Colon Cancer in the Background of Adenomatous Polyposis Coli Inactivation

Casitas B-lineage lymphoma (c-Cbl) is a recently identified ubiquitin ligase of nuclear β-catenin and a suppressor of colorectal cancer (CRC) growth in cell culture and mouse tumor xenografts. We hypothesized that reduction in c-Cbl in colonic epithelium is likely to increase the levels of nuclear β-catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APC(Δ14/+)) mouse model. Haploinsufficient c-Cbl mice (APC(Δ14/+) c-Cbl(+/−)) displayed a significant (threefold) increase in atypical hyperplasia and adenocarcinomas in the small and large intestines; however, no differences were noted in the adenoma frequency. In contrast to the APC(Δ14/+) c-Cbl(+/+) mice, APC(Δ14/+) c-Cbl(+/−) crypts showed nuclear β-catenin throughout the length of the crypts and up-regulation of Axin2, a canonical Wnt target gene, and SRY-box transcription factor 9, a marker of intestinal stem cells. In contrast, haploinsufficiency of c-Cbl(+/−) alone was insufficient to induce tumorigenesis regardless of an increase in the number of intestinal epithelial cells with nuclear β-catenin and SRY-box transcription factor 9 in APC(+/+) c-Cbl(+/−) mice. This study demonstrates that haploinsufficiency of c-Cbl results in Wnt hyperactivation in intestinal crypts and accelerates CRC progression to adenocarcinoma in the milieu of APC(Δ14/+), a phenomenon not found with wild-type APC. While emphasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial loss of c-Cbl and inactivation of APC significantly contribute to CRC tumorigenesis.