Elsevier

Journal of Hepatology

Volume 59, Issue 5, November 2013, Pages 1107-1117
Journal of Hepatology

Review
Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs

https://doi.org/10.1016/j.jhep.2013.07.001Get rights and content
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open access

Summary

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late when the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates of pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects.

Abbreviations

HCC
hepatocellular carcinoma
FZD
frizzled
CSC
cancer stem cells
PCP
planar cell polarity
TCF/LEF
T-cell factor/lymphoid enhancer factor
TLE-1
transducin like enhancer-1
APC
adenomatous polyposis coli protein
GSK3β
glycogen synthase kinase 3β
CK1
casein kinase 1
β-TRCP
beta-transducin repeat containing protein
SCF
Skp1/cullin F-box complex
Dvl/Dsh
disheveled
Pygo
pygopus
CBP
CREB-binding protein
PKC
protein kinase C
NFAT
nuclear factor of activated T cell
NLK
Nemo-like kinase
Wif1
Wnt inhibitory protein-1
sFRP
secreted FZD-related proteins
Dkk
Dickkopf
Krm
Kremen
Rspo
R-spondin
Gpc3
glypican-3
DIFs
differentiation-inducing factors

Keywords

Hepatocellular carcinoma
Therapy
Wnt pathway
Drug discovery

Cited by (0)

These authors contributed equally to this work.