Role of Wnt/β-catenin signaling in liver metabolism and cancer

Abstract

Wnt/β-catenin signaling is known for its role in embryogenesis as well as carcinogenesis. In the liver, it plays many critical roles during hepatic development and regeneration, and its dysregulation is evident in aberrant hepatic growth during various liver tumors. Its chief cellular roles in the liver include regulation of processes of cell proliferation, apoptosis, oxidative stress and differentiation, which in turn contributes to hepatic growth, zonation, xenobiotic metabolism and other metabolic processes inherent to the liver. Most of these functions of the Wnt/β-catenin signaling are dictated through the highly temporal and tissue-specific or non-specific transcriptional targets of the pathway. In addition, some of the critical functions such as cell-cell adhesion and perhaps maintenance of various junctions that are critical from an epithelial cell biology perspective are also a function of β-catenin, which is the central component of the canonical Wnt pathway. Various animal models and clinical studies have demonstrated the spectra of Wnt/β-catenin signaling in liver health and disease. Thus therapeutic modulation of this pathway for improved hepatic health is inevitable in the future. The current review discusses the advances in our understanding of the Wnt/β-catenin signaling in liver physiology and pathology especially in hepatic metabolism and various tumors in adult liver and goes on to extrapolate the pre-clinical significance and possible translational implications of such findings.

Figure 1

A simplified schematic of Wnt/beta-catenin signaling.

Figure 2

Beta-catenin target genes in the liver: role in cell proliferation and metabolism.

1. Loss of beta-catenin in the liver (conditional knockout or KO) leads to decreased gene expression of cyclin-D1 and numbers of hepatocytes in S-phase in as shown by immunohistochemistry for Ki-67, as compared to littermate controls (Con).

2. Loss of beta-catenin leads to loss of GS in KO, whereas a single layer of hepatocytes (arrowhead) around central vein is positive in Con liver.

Figure 3

Stabilization and nuclear translocation of β-catenin is observed in HCC.

1. Normal livers display β-catenin predominantly at the hepatocyte membrane.

2. An increase in total β-catenin and its nuclear translocation (arrowhead) is observed in a representative HCC liver sample.