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