Year: 2013
Type: article
Abstract: β-Catenin is important in liver homeostasis as a part of Wnt signaling and adherens junctions (AJs); however, aberrant β-catenin activation is observed in a subset of hepatocellular carcinomas (HCC). Since therapeutic targeting of β-catenin in HCC is inevitable, it is important to investigate the implications of such interventions on AJs. We address this important issue both in vivo and in vitro. We observed that hepatocyte-specific β-catenin knockout (βKO) mice have no noticeable adhesive defects. We identified an increase in γ-catenin at AJs in βKO livers. We further observed that γ-catenin was unable to translocate to the nucleus in absence of β-catenin after partial hepatectomy in βKO mice. Since γ-catenin is a desmosomal protein, we next investigated if γ-catenin changes in βKOs were at the expense of desmosomes. We did not observe any differences on desmosomal structure or composition in βKO livers. Similarly, as some tight junction components are β-catenin target genes, we observed only minor changes in tight junctions, such that the function of the junctions was not affected in vivo. To further determine the role and regulation of γ-catenin in absence of β-catenin we established an in vitro model. Hep3B human HCC cells transfected with siRNA to β-catenin led to γ-catenin increase. Using this model we showed γ-catenin was unable to rescue decreased Wnt reporter activity. Scratch-wound assays showed β- and γ-catenin single knockdowns did not affect cell migration, but double knockdown significantly increased wound closure. Centrifugal assay for cell adhesion and hanging-drop assays, measuring hetero- and homotypic cell-cell interactions, showed significant decreases in adhesive strength with double knockdown only. Lastly, we showed the increased γ-catenin with β-catenin loss appears to be regulated by the serine/threonine phosphorylation of γ-catenin by protein kinase A, introducing the possibility of a catenin sensing mechanism. In conclusion, β-catenin loss is compensated by γ-catenin at AJs without negatively affecting other junctions; however, the function of β-catenin as part of the Wnt pathway remains unfulfilled by γ-catenin. Thus, proposed anti-β-catenin therapies for HCC may be able to target aberrant β-catenin in Wnt signaling specifically without negatively affect HCC prognosis, as long as γ-catenin is spared.
Author: Emily Wickline
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W108786763