C-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/?-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.

ABSTRACT: The proto-oncogene ?-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear ?-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear ?-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target ?-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear ?-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear ?-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/?-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/?-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

SUBMITTER: Kumaradevan S 

PROVIDER: S-EPMC6099425 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature