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J Hepatol. 2013 Nov;59(5):1107-17. doi: 10.1016/j.jhep.2013.07.001. Epub 2013 Jul 5.

Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs.

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1
INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69008 Lyon, France; Université Lyon-1, F-69622 Villeurbanne, France; Centre Léon Bérard, F-69008 Lyon, France.

Abstract

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.

KEYWORDS:

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

PMID:
23835194
DOI:
10.1016/j.jhep.2013.07.001
[Indexed for MEDLINE]
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