You are here

Article Text

Article menu
Download PDFPDF
Commentary
MAPping the Wnt pathway to hepatocellular carcinoma recurrence
  1. Béatrice Benoit1,
  2. Christian Poüs1,2
  1. 1 INSERM UMR-S 1193, Faculté de Pharmacie Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
  2. 2 APHP, Biochimie-Hormonologie, Hôpital Antoine Béclère, Hôpitaux universitaires Paris-Sud, Clamart, France
  1. Correspondence to Dr Christian Poüs, INSERM UMR-S 1193, Faculty of Pharmacy, 5 rue JB Clement, Chatenay-Malabry 92296, France; christian.pous{at}u-psud.fr

http://dx.doi.org/10.1136/gutjnl-2016-311637

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Early recurrence is a frequent cause of poor survival after hepatocellular carcinoma (HCC) resection. At the cell level, efforts to link HCC with the dysfunction of signalling pathways identified several alterations, especially in the Wnt/β-catenin pathway.1 Wnt signalling controls the balance between cell proliferation and differentiation and its regulation relies partly on subcellular compartmentalisation at the plasma membrane in late endosomes and/or on the cytoskeleton (see refs. 2 ,3 for reviews) (figure 1A).

    Figure 1

    The Wnt/β-catenin pathway: regulation by subcellular compartmentalisation and links with the cell cycle through the involvement of Protein Regulator of Cytokinesis 1 (PRC1). (A) (1) The β-catenin destruction complex, which comprises adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), functions to phosphorylate free β-catenin, allowing its recognition by the E3 enzyme β-Transducin repeats-Containing Protein (β-TrCP) and its consecutive degradation by the proteasome. (2) The lipoprotein receptor-related protein (LRP)5/6 signalosome: Wnt agonist binding to its receptor complex (Frizzled+LRP5/6) allows LRP5/6 phosphorylation, Axin and Microtubule-Actin Crosslinking Factor 1 (MACF1) recruitment to the signalosome and then inactivation of GSK3β. (3) APC motorisation towards the microtubule plus ends allows its interaction with end-binding 1 (EB1) and mDia to stabilise microtubules at the migrating cell front. (4) Cytoplasmic PRC1 binds to microtubule bundles and interacts with the destruction complex to inactivate it. (5) Inactivation of the destruction complex leads to β-catenin nuclear entry and association with the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor to promote gene expression. (6) Nuclear localisation of Axin, APC, Dishevelled (Dvl) and PRC1 modulates the Wnt/β-catenin signalling pathway. Nuclear APC competes with TCF/LEF for binding to β-catenin and favours its nuclear export. Nuclear Axin binds to the promoter region and competes with the binding of the β-catenin transcription complex on the promoter of target genes …

    View Full Text

    Footnotes

    • Contributors Both authors contributed to article design and writing.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; internally peer reviewed.

    Linked Articles