c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors
Metrics: PDF 2311 views | HTML 2489 views | ?
Moshe Shashar1, Jamaica Siwak1, Umit Tapan2, Shin Yin Lee2, Rosana D. Meyer3, Paige Parrack1, Josenia Tan3, Fatemeh Khatami1, Jean Francis1, Qing Zhao3, Kevan Hartshorn2, Vijaya B. Kolachalama4,5, Nader Rahimi3 and Vipul Chitalia1,4
1 Department of Medicine, Boston University School of Medicine, Boston, MA, USA
2 Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA
3 Department of Pathology, Boston University School of Medicine, Boston, MA, USA
4 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
5 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA
Vipul Chitalia, email:
Keywords: colorectal cancer, Cbl, Wnt
Received: June 16, 2016 Accepted: August 21, 2016 Published: September 20, 2016
Despite the loss of Adenomatous Polyposis Coli (APC) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl’s mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.