Wnt/β-catenin signaling pathway in liver biology and tumorigenesis

The Wnt/beta-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/beta-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/beta-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with beta-catenin mutations, which activate Wnt/beta-catenin signaling. HCCs with activation of the Wnt/beta-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/beta-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/beta-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.