Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest human cancers. Activating mutations in the telomerase reverse transcriptase (TERT) promoter (TERTp) and CTNNB1 gene encoding β-catenin are widespread in HCC (~50% and ~30%, respectively). TERTp mutations are predicted to increase TERT transcription and telomerase activity. This review focuses on exploring the role of TERT and β-catenin in HCC and the current findings regarding their interplay. TERT can have contradictory effects on tumorigenesis via both its canonical and non-canonical functions. As a critical regulator of proliferation and differentiation in progenitor and stem cells, activated β-catenin drives HCC; however, inhibiting endogenous β-catenin can also have pro-tumor effects. Clinical studies revealed a significant concordance between TERTp and CTNNB1 mutations in HCC. In stem cells, TERT acts as a co-factor in β-catenin transcriptional complexes driving the expression of WNT/β-catenin target genes, and β-catenin can bind to the TERTp to drive its transcription. A few studies have examined potential interactions between TERT and β-catenin in HCC in vivo, and their results suggest that the coexpression of these two genes promotes hepatocarcinogenesis. Further studies are required with vertebrate models to better understand how TERT and β-catenin influence hepatocarcinogenesis.
Highlights
Hepatocellular carcinoma (HCC) forms 80% of all primary liver cancers and is the fourth leading cause of cancer-related mortality globally
In embryonic stem and progenitor cells, the Telomerase reverse transcriptase (TERT) and WNT/βcatenin signaling axes crosstalk such that TERT enhances the transcription of β-catenin target genes, while β-catenin enhances the transcription of TERT by binding to its promoter region [3,4]
This review focuses on current advances in delineating the role of TERT and CTNNB1 in HCC and the relationship between these two genes during carcinogenesis
Summary
Hepatocellular carcinoma (HCC) forms 80% of all primary liver cancers and is the fourth leading cause of cancer-related mortality globally. Telomerase reverse transcriptase (TERT), TP53 (tumor protein p53), and CTNNB1 encoding β-catenin are the top three most frequently mutated genes in HCC, altered in 47.1%, 29.2%, and 27.4% of cases from large-scale sequencing projects [2]. Both TERT and β-catenin play essential roles in liver development, tumorigenesis, and stemness pathways. TERT is involved in many roles independent of its telomere lengthening activity [11] These non-canonical functions of TERT include regulating gene expression, signal transduction, mitochondrial metabolism, and resistance to ionizing radiation [12]. Enhancer of activated B cells; and VEGF, vascular endothelial growth factor
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