Hepatocellular carcinoma is the sixth most common cancer worldwide. In the majority of cases, there is evidence of existing chronic liver disease from a variety of causes including viral hepatitis B and C, alcoholic liver disease and nonalcoholic steatohepatitis. Identification of the signalling pathways used by hepatocellular carcinoma cells to proliferate, invade or metastasize is of paramount importance in the discovery and implementation of successfully targeted therapies. Activation of Wnt/β-catenin, Notch and Hedgehog pathways play a critical role in regulating liver cell proliferation during development and in controlling crucial functions of the adult liver in the initiation and progression of human cancers. β-catenin was identified as a protein interacting with the cell adhesion molecule E-cadherin at the cell-cell junction, and has been shown to be one of the most important mediators of the Wnt signalling pathway in tumourigenesis. Investigations into the role of Dikkopf-1 in hepatocellular carcinoma have demonstrated controversial results, with a decreased expression of Dickkopf-1 and soluble frizzled-related protein in various cancers on one hand, and as a possible negative prognostic indicator of hepatocellular carcinoma on the other. In the present review, the authors focus on the Wnt⁄β-catenin, Notch and Sonic Hedgehog pathways, and their interaction with Dikkopf-1 in hepatocellular carcinoma.

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Abstract. Recent evidence has suggested that downregulation of the Wnt/β-catenin signaling pathway may contribute to the development and growth of HCC. Consequently, elements of this pathway have begun to emerge as potential targets for improving outcomes of anti-HCC. Thus, the present study sought to examine the effects of Wnt-1 blockade using the classical diethylnitrosamine (DEN)-induced chemical carcinogenesis mouse model of HCC. The depletion of Wnt-1 using neutralizing antisera was done for ten consecutive days at the age of 9 months and mice were examined for the following 20 days. At that time, DEN-treated mice had multiple variably-sized hepatic cell adenomas. Anti-Wnt-1 was particularly potent in suppressing the expression of critical elements of the Wnt/β-catenin signaling pathway, such as β-catenin and Frizzled-1 receptor, however, not Dickkopf-related protein 1. This effect co-existed with the suppression of Cyclin D1, FOXM1, NF-κΒ and c-Jun commensurate with proliferation and apoptosis blockade in hepatocellular adenomas, and reduced Bcl-2 and c-Met in the serum of mice. Nonetheless, tumor size and multiplicity were found to be unaffected, suggesting that apoptosis may be equally important to proliferation in the context of counteracting DEN induced hepatocellular adenomas of mice.