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Review
. 2019 Jul 2;11(7):926.
doi: 10.3390/cancers11070926.

Wnt/β-Catenin Signaling in Liver Cancers

Wenhui Wang  1 , Ron Smits  2 , Haiping Hao  3 , Chaoyong He  4
Affiliations
Review

Wnt/β-Catenin Signaling in Liver Cancers

Wenhui Wang et al. Cancers (Basel). .

Abstract

Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. Liver cancer consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and several other rare tumors. Progression has been witnessed in understanding the interactions between etiological as well as environmental factors and the host in the development of liver cancers. However, the pathogenesis remains poorly understood, hampering the design of rational strategies aiding in preventing liver cancers. Accumulating evidence demonstrates that aberrant activation of the Wnt/β-catenin signaling pathway plays an important role in the initiation and progression of HCC, CCA, and HB. Targeting Wnt/β-catenin signaling potentiates a novel avenue for liver cancer treatment, which may benefit from the development of numerous small-molecule inhibitors and biologic agents in this field. In this review, we discuss the interaction between various etiological factors and components of Wnt/β-catenin signaling early in the precancerous lesion and the acquired mechanisms to further enhance Wnt/β-catenin signaling to promote robust cancer formation at later stages. Additionally, we shed light on current relevant inhibitors tested in liver cancers and provide future perspectives for preclinical and clinical liver cancer studies.

Keywords: CCA; HB; HCC; Wnt/β-catenin signaling; liver cancer; precancerous lesion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Wnts are lipid-modified by PORCN in the ER and escorted by WLS from the Golgi to the plasma membrane for secretion. In the absence of Wnt ligands due to Wnt antagonists (WIF, DKK, and SFRP) and Kallistatin, β-catenin is phosphorylated by a destruction complex consisting of GSK3, CK1, APC and AXIN. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination. In the nucleus, the TCF/LEF transcription factor activity is repressed by transducin-like enhancer of split (TLE) and histone deacetylase (HDAC). Association of Wnt ligands with their receptors leads to the dissociation of the destruction complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF and co-activators such as CBP/300, BCL9, and Pygo.
Figure 2
Figure 2
Dynamic activation of Wnt/β-catenin signaling from risk factor exposure to final liver cancer.
See this image and copyright information in PMC

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