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.

Figure 1. Canonical Wnt/β-catenin signaling pathway in HCC.

(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.