β-Catenin signaling in hepatocellular carcinoma
Chuanrui Xu, … , Diego F. Calvisi, Xin Chen
Chuanrui Xu, … , Diego F. Calvisi, Xin Chen
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e154515. https://doi.org/10.1172/JCI154515.
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Review

β-Catenin signaling in hepatocellular carcinoma

Abstract

Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.

Authors

Chuanrui Xu, Zhong Xu, Yi Zhang, Matthias Evert, Diego F. Calvisi, Xin Chen

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Figure 1

Canonical Wnt/β-catenin signaling pathway in HCC.

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Canonical Wnt/β-catenin signaling pathway in HCC. (A) When Wnt ligands a...
(A) When Wnt ligands are present, Wnt/FZD signaling activation leads to the phosphorylation of mammalian homolog of dishevelled (DVL). Phosphorylated DVL recruits AXIN and GSK3β to the plasma membrane, hence blocking the degradation complex’s formation. Subsequently, β-catenin accumulates in the cytoplasm and then translocates into the nucleus. Nuclear β-catenin binds to TCF/LEF transcription factors and promotes the transcription of target genes. (B) When Wnt ligands are absent, soluble β-catenin is phosphorylated by the GSK3β-CK1α-APC-AXIN1 complex. Once phosphorylated, β-catenin is degraded by the proteasome after ubiquitination by the Skp-, Cullin-, and F-box–containing (SCF) protein complex. When β-catenin is absent in the nucleus, the TCF/LEF transcription factors are repressed by TLE-1. CTNNB1 (encoding β-catenin), AXIN1, and APC are mutated in 27%, 8%, and 3% of human HCCs, respectively.