ABSTRACT
Although the involvement of b-catenin in tumor development was fi rst observed in colon cancer, a multitude of studies have shown activation of Wnt/b-catenin pathway in various other human malignancies, including breast, cervix, ovary, prostate, kidney, lung, skin, stomach and liver cancer (Luu et al. 2004). Mounting evidence suggests that hyperactivation of Wnt pathway or dysregulation of specifi c pathway components occur in approximately 50% of all human cancers (Goss and Khan 2011). In 1998, de La Coste and colleagues fi rst observed the role of Wnt/b-catenin signaling in HCC. Since then, an aberrant activation of Wnt/b-catenin signaling has been reported in a wide variety of HCC patients. Th e nuclear and/or cellular accumulation of b-catenin, best observed in HCC samples by immunohistochemical staining, has been accepted as the reminiscent of activated Wnt/b-catenin signaling. In 33-67% of HCC patients, nuclear and/or cellular accumulation of b-catenin have been strongly associated with poorly diff erentiated tumor with high proliferative activity, vascular invasion and dismal prognosis (Endo et al. 2000; Wong et al. 2001; Inagawa et al. 2002; Coleman 2003). Additionally, a strong correlation has been established between nuclear accumulations of b-catenin with mutations (Wong et al. 2001). Accumulating studies reveal mutation of b-catenin gene (CTNNB1) leading to its nuclear and/or cytoplasmic localization in 20-40% of all HCC cases (Nejak-Bowen and Monga 2011). Interestingly, a higher frequency of b-catenin mutations in HCC associated with HCV infections have been observed than HBV infections or alcoholic risk factors (Hsu et al. 2000; Wong et al. 2001; Huang et al. 1999; Edamoto et al. 2003). Several studies indicate that b-catenin mutation and accumulation occur during the progression of HCC rather than early hepatocarcinogenic events (Inagawa et al. 2002; Kondo et al. 1999; Nhieu et al. 1999; Joo et al. 2003). Most of the mutations in HCC frequently occur within a single exon (exon 3) of CTNNB1 gene, which is responsible for the phosphorylation and subsequent ubiquitination of b-catenin. Consequently, mutations in this region culminate in stabilization and nuclear accumulation. Immunohistochemically detected expression of GS has been found to be a sensitive and specifi c marker of b-catenin-mutated HCC (Cadoret et al. 2002; Zucman-Rossi et al. 2007). Moreover, alterations in the other components of the Wnt/b-catenin pathway, such as mutations in the components of the degradation complex of b-catenin, including AXIN1 and AXIN2, inactivation of Axin and GSK-3b as well as overexpression of FZD7 receptor, lead to wildtype b-catenin stabilization (Zucman-Rossi et al. 2007; Taniguchi et al. 2002; Ban et al. 2003; Merle et al. 2004).
