Expression of mutant nuclear β-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis

Abstract

beta-catenin has functions both in the cadherin-mediated cell adhesion system and in the signalling pathway that mediates dorsal axis patterning in the embryo; it has been shown to be aberrantly expressed or mutated in diverse types of human tumour, but the biological significance of this remains to be clarified. To elucidate the clinical implications of aberrant beta-catenin expression and the potential differences between mutant and wild-type beta-catenin protein expression in hepatocellular carcinoma (HCC), the protein expression was analysed by immunohistochemical staining, supplemented by the analysis of gene mutation. Among 372 unifocal primary HCCs, beta-catenin was detected in the tumour cell membrane alone in 272 tumours (group A) and also in the nuclei in 100 (group B). In group A, 148 tumours had decreased beta-catenin expression, but the reduction did not correlate with invasion or prognosis. When compared with group A, however, group B had significantly lower frequencies of hepatitis B surface antigen carrier (p=0.015), and alpha-fetoprotein elevation (p=0.0003), but more often had non-invasive HCC (p<0.001) and better survival (p=0.01). Nuclear beta-catenin expression strongly correlated with mutation of the gene (p<0.00001). In group B, HCC with mutant nuclear beta-catenin correlated positively with non-invasive (stage 1) tumour and inversely with portal vein tumour thrombi (stage 3 HCC), and had significantly better 5-year survival, p<0.001 and p<0.0003, respectively. These results suggest that beta-catenin mutation plays an important role in the tumourigenesis of a subset of HCC of good prognosis, and that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent.

Genetic mechanisms of hepatocarcinogenesis

“…In addition, an early role for Wnt activation in hepatocarcinogenesis comes from observations that transgenic mice expressing an oncogenic (mutated) form of b-catenin rapidly develop hepatomegaly (Cadoret et al, 2001), demonstrating that constitutively activated b-catenin strongly stimulates hepatocellular growth in vivo. However, mutant bcatenin is not associated with metastases among HCC patients (Mao et al, 2001), which also suggests that it is an early target in hepatocarcinogenesis. Interestingly, the inhibition of the proteasome by HBxAg (Huang et al, 1996) may block the normal degradation of wild type b-catenin, resulting in its stabilization and accumulation at the early stages of tumor development, although there is presently no data to support this mechanism.…”

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…Involvement of the canonical and non-canonical Wnt pathway in liver oncogenesis has been described by various investigators [59][60][61][62][63][64][65][66][67]. One of the most frequently described mechanisms for activation of the canonical signaling pathway in HCC involves activation of β-catenin through mutations in the CTNNB1 gene.…”

Genetics of hepatocellular tumors

“…However, this result has to be confirmed in a second study. Finally, b-catenin-activating mutations were found most frequently in large sized Wong et al, 2001) and well-differentiated tumors (Mao et al, 2001). Although the pathological tumor-node-metastasis staging has been applied clinically to HCC patients, this system is inadequate for predicting recurrence in individuals who undergo hepatic resection.…”