Exon 3 mutations of CTNNB1 drive tumorigenesis: a review

Abstract

The canonical Wnt/β-catenin signaling pathway, an important modulator of progenitor cell proliferation and differentiation, is highly regulated for the maintenance of critical biological homeostasis. Decades of studies in cancer genetics and genomics have demonstrated that multiple genes encoding key proteins in this signaling pathway serve as targets for recurrent mutational alterations. Among these proteins, β-catenin and adenomatosis polyposis coli (APC) are two key nodes. β-catenin contributes in transporting extracellular signals for nuclear programming. Mutations of the CTNNB1 gene that encodes β-catenin occur in a wide spectrum of cancers. These mutations alter the spatial characteristics of the β-catenin protein, leading to drastic reprogramming of the nuclear transcriptional network. Among the outcomes of this reprogramming are increased cell proliferation, enhanced immunosuppression, and disruption of metabolic regulation. Herein we review the current understanding of CTNNB1 mutations, their roles in tumorigenesis and discuss their possible therapeutic implications for cancer.

Keywords: CTNNB1; Wnt/β-catenin signaling pathway; immunosuppression; mutations; β-catenin.

Figure 1. The biological roles of β-catenin in the Wnt/β-catenin signaling pathway

This pathway has two states dependent upon the presence or absence of Wnt ligands. When Wnt ligands are absent, β-catenin is phosphorylated by the destruction complex and degraded. When Wnt ligands are present, β-catenin is not degraded and translocates to the nucleus and functions as a transcription factor.

Figure 2. The primary structure of β-catenin and its relevant binding sites

β-catenin has three domains: a 550-amino-acid central repeat domain, an approximately 150-amino-acid N-terminal domain, and an approximately 100-amino-acid C-terminal domain. They are binding sites for E-cadherin, GSK-3β/CK-1, and TCF/LEF, respectively, and exert different roles.

Figure 3. The relationship between β-catenin and immunosuppression in the tumor microenvironment

Cancer cells can induce relevant immunosuppressive molecules and cells, such as TGF-β, IL-10, indoleamine 2,3-dioxygenase (IDO), Tregs, and regulatory DCs. They can inhibit T cells, which have toxic effects on cancer cells. Also, cancer-intrinsic β-catenin signaling can decrease T-cell infiltration. β-catenin also helps cancer cells secrete immunosuppressive molecules.

Figure 4. The relationship between Wnt/β-catenin signaling pathway and glucose metabolism in cancer cells

The Wnt/β-catenin signaling pathway can induce the Warburg effect and then promote cancer cell survival. Cancer cells prefer to use the Warburg effect to satisfy their energy demands regardless of the presence or absence of oxygen.