title: c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors.
abstract: 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.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Shashar
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Jamaica
authors.initials: J
authors.lastname: Siwak
authors.affiliation: Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Umit
authors.initials: U
authors.lastname: Tapan
authors.affiliation: Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Shin Yin
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Rosana D
authors.initials: RD
authors.lastname: Meyer
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Parrack
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Josenia
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Khatami
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Francis
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Kevan
authors.initials: K
authors.lastname: Hartshorn
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.|Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Kolachalama
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Vipul
authors.initials: V
authors.lastname: Chitalia
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D050721:Proto-Oncogene Proteins c-cbl / Q000032:analysis / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse
keywords: Wnt; colorectal cancer; Cbl