A Complex Interplay between Wnt/β-Catenin Signalling and the Cell Cycle in the Adult Liver

Abstract

Canonical Wnt signalling, governed by its effector β-catenin, is known for a long time as playing an important role in development, tissue homeostasis, and cancer. In the liver, it was unravelled as both an oncogenic pathway involved in a subset of liver cancers and a physiological signalling identified as the "zonation-keeper" of the quiescent liver lobule. This duality has encouraged to explore the role of canonical Wnt in liver regeneration and liver-cell proliferation mainly using murine genetic models of β-catenin overactivation or inactivation. These studies definitely integrate Wnt signalling within the hepatic network driving regeneration and proliferation. We will review here the current knowledge concerning the mitogenic effect of Wnt, to switch on its specific role in the liver, which is quiescent but with a great capacity to regenerate. The duality of β-catenin signalling, associated both with liver quiescence and liver-cell proliferation, will be brought forward.

Figure 1

Wnt signalling in the adult quiescent liver and in CTNNB1-mutated HCCs. (a) The liver-cell plate and its portocentral organization; (b) the periportal hepatocyte is deprived of Wnt signalling, due to its high amount of Apc, allowing the destruction complex to be efficient to degrade β-catenin. The pericentral hepatocyte has a Wnt-dependent β-catenin signalling, while in HCCs it is constitutively activated due to mutations in phosphorylation residues in CTNNB1; (c) the output of the transcriptional β-catenin is metabolic in the pericentral hepatocyte, while it is both metabolic and mitogenic in HCCs.

Figure 2

Hypothesis for a crosstalk between β-catenin and Ras signalling pathways to control hepatocyte proliferation. (a) In the quiescent liver, phospho-erk signaling is described as being periportal, while β-catenin is pericentral; (b) no cyclin D1 mRNA is detected in these conditions; (c) 24 h after 2/3 hepatectomy, there is an extension in the β-catenin and the ras activation territories. We now hypothesize that it could generate a common territory in which both which phospho-erk and β-catenin signalings are activated; (d) this can be exemplified by cyclin D1, which is a target of β-catenin, potentiated by ras signaling. Its localization after hepatectomy is restricted to the midlobular region. PV = portal vein; CV = central vein.