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.
Highlights
In the United States, the lifetime risk for colorectal cancers (CRC) is as high as 5% [1]
Lossof-function APC mutations that are common in a majority of sporadic CRC and familial adenomatous polyposis coli (APC) patients are linked to Wnt hyperactivation
CRC pathogenesis is driven by Wnt hyperactivation primarily due to active nuclear β-catenin due to APC loss or CTNNB1 activating mutations, a state that is analogous to persistent Wnt-on phase
Summary
In the United States, the lifetime risk for CRC is as high as 5% [1]. It is the second and the third most common cause of cancer death in men and women, respectively, and regulators of its pathogenesis are important to discern [1]. In a small subgroup of patients with wild-type APC, Wnt hyperactivation is due to a gain-of-function CTNNB1 (β-catenin) mutation. Both APC loss and the mutant β-catenin increase the transcriptionally ‘active’ β-catenin in the nucleus and are considered being ‘tumorigenic’ and the key initiators of CRC pathogenesis [2,3,4]. CRC pathogenesis is driven by Wnt hyperactivation primarily due to active nuclear β-catenin due to APC loss or CTNNB1 activating mutations, a state that is analogous to persistent Wnt-on phase. As c-Cbl is known to target β-catenin in Wnt-on phase [16, 17] and given the central role of active β-catenin in CRC tumorigenesis, we decided to examine the functional importance of c-Cbl in CRC. The image quantification technique developed for this work has the potential for broad functionality and can be extended to estimate several aspects from histopathological images derived from heterogeneous tissues such as cancer
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