Correlation between β-catenin mutations and expression of Wnt-signaling target genes in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most frequent cancer worldwide (for review see [1,2]). During the last years it became obvious that active Wnt-signaling as characterized by the presence of nuclear/cytosolic β-catenin highly correlates with the occurrence of HCC in animal models and in human patients [3-6]. Under normal conditions the activated (nuclear) form of β-catenin is a transcriptional activator mainly involved in the regulation of cell proliferation, differentiation and stem cell maintenance [7-9]. As a transcriptional regulator β-catenin interacts with members from the LEF-1/TCF transcription factor family, probably by removal of co-repressors like groucho [10-12]. It should be noted that LEF-1/TCF is an architectural transcription factor that upon binding to its target sequence together with corepressors and in the absence of β-catenin inhibits expression.In differentiated, non-proliferating cells, β-catenin is associated with membrane bound E-cadherin [13] and non-bound molecules are quickly removed from the cytosol in the absence of Wnt-signaling, thereby preventing its translocation to the nucleus. This is accomplished by a multienzyme complex that binds cytosolic β-catenin. When bound to the complex β-catenin is phosphorylated by active glycogen synthase kinase 3β(GSK3β), then labelled by ubiquitinylation and finally degradated by the proteasome. The complex, in addition to GSK3β, contains other proteins like Axin1, Casein Kinase Iα (CKIα) and APC (Adenomatous Polyposis Coli protein) (for review see [14]). Although mutations in each of the components of the complex may cause abnormal cytosolic stabilization of β-catenin, mutations of the β-catenin gene itself appear to be the most common cause for stabilization in pathological situations. These mutations usually affect residues at position 33 (S), 37 (S), 41 (T) or 45 (S) located in exon 3 of the human β-catenin gene that are the targets of priming phosphorylation by CKIα (S45) or subsequent phosp