Journal
JOURNAL OF HEPATOLOGY
Volume 54, Issue 2, Pages 288-299Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2010.06.033
Keywords
Hepatocellular carcinoma; Frizzled; Dishevelled; Targeted therapy
Categories
Funding
- CLARA
- ARC [3676]
- EZUS Lyon
- Association Francaise de l'Etude du Foie (AFEF
- INSERM
- Institut National de la Sante Et de la Recherche Medicate (INSERM)
- Agence Nationale de la Recherche (ANR)
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Background & Aims: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. Methods: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their antineoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. Results: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to beta-catenin degradation and PKC delta. activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. Conclusions: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve beta-catenin and PKC delta modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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