Wnt signaling in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. As in many other types of cancer, aberrant activation of the canonical Wnt/beta-catenin signaling pathway is an important contributor to tumorigenesis. In HCC this frequently occurs through mutations in the N-terminal region of beta-catenin that stabilize the protein and permit an elevated level of constitutive transcriptional activation by beta-catenin/TCF complexes. In this article we review the abundant evidence that Wnt/beta-catenin signaling contributes to liver carcinogenesis. We also discuss what is known about the roles of Wnt signaling in liver development, regeneration, and stem cell behavior, in an effort to understand the mechanisms by which activation of the canonical Wnt pathway promotes tumor formation in this organ. The Wnt/beta-catenin pathway presents itself as an attractive target for developing novel rational therapies for HCC, a disease for which few successful treatment strategies are currently available.

Figure 1

Key components of the Wnt/β-catenin signaling pathway. Proteins shaded in gray have an inhibitory effect on the stability of β-catenin and its accumulation in the nucleus. Unshaded components have a positive influence on Wnt/β-catenin signaling. See text for details.

Figure 2

Zonation of hepatocytes within liver lobules reflects the level of Wnt/β-catenin signaling. Hepatocytes are organized in lobules around a central vein, and branches of the hepatic artery (HA), bile duct (BD), and hepatic portal vein (PV) are located at the periphery of each lobule. Expanded view of a single row of hepatocytes within a lobule showing the perivenous zone (pale blue), in which β-catenin is detected by IHC, and the periportal zone (green) in which APC is detected [45]. Enzymes associated with distinct metabolic functions, such as glutamine synthase (GS) and carbamoylphosphate synthase 1 (CPS1) are expressed in gradients (gray triangles).

Figure 3

Distribution and frequency of β-catenin missense mutations leading to activation of canonical Wnt signaling in HCC. Specific amino acid residues of β-catenin are indicated by their position number and single letter code.