Molecular Signalling in Hepatocellular Carcinoma: Role of and Crosstalk among Wnt/β-Catenin, Sonic Hedgehog, Notch and Dickkopf-1

Abstract

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.

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

“…Hepatocellular carcinoma (HCC) is the most common type of liver cancer and among leading causes of cancer-related death of humans (1)(2)(3). Rodent models of HCC have been proven useful in revealing aspects of its multistep pathogenesis and preclinical testing of anti-HCC treatments (1,2).…”

“…Their binding to the transmembrane Frizzled (FZD) receptors activates the Wnt/β-catenin pathway that eventually results in the cytoplasmic accumulation and nuclear translocation of the β-catenin protein (11)(12)(13). Intranuclear β-catenin binding to T-cell factor 4 (Tcf4) consequently upregulates the expression of many different cancer-related genes, including c-myc and Cyclin-D1 (3,14).…”

“…Activating mutations of the β-catenin gene (CTNNB1), loss-of-function mutations in APC and Axin, as well as deregulation of other Wnt/β-catenin pathway elements [ligands, such as Wnt-1; receptors and co-receptors, such as Frizzled-1 (FZL-1), and inhibitors, such as DKK1] have all been implicated in HCC (3,(8)(9)(10)(11)(12)(13). Wnt/β-catenin as well as other molecular pathways of HCC interrelate with important inflammation, proliferation and apoptosis molecules, such as Forkhead box M1 (FOXM1), NF-κB, c-Jun and B-cell lymphoma 2 (Bcl-2) with important roles in HCC evolution and growth (15)(16)(17)(18)(19).…”

Molecular mechanisms of niclosamide antitumor activity

“…3) выполняет важную роль в эмбриогенезе и развитии злокачественных новообразований, включая гепатоканцерогенез [20,21].…”

SULF1/SULF2 reactivation during liver damage and tumour growth

“…Liver tumours like most other cancers promote tumour growth by activating a number of cell signalling pathways (Giakoustidis A et al 2015). Most growth promoting cell signalling pathways do not only require ligand receptor interaction but also heparan sulfate proteoglycan (HSPG) co-receptor participation to facilitate ligand/receptor interaction (Merry and Gallagher 2002).…”