Two of the most common genetic alterations in liver cancer have been shown to act as powerful partners in crime, according to a new study published in Cancer Cell International. Researchers at Kyung Hee University in South Korea report that mutations in the CTNNB1 gene, which encodes the β-catenin protein, cooperate with mutations in the promoter of the TERT gene, which encodes the catalytic component of telomerase, to dramatically accelerate the formation of hepatocellular carcinoma, the most common form of primary liver cancer. The study, led by Hyunjung Park, Jaehun Lee, Hyuk Moon and Simon Weonsang Ro, demonstrates that this cooperation is driven by activation of the MAPK/ERK signaling pathway, a finding that could open new therapeutic avenues for a molecular subset of liver cancer patients who currently have limited targeted treatment options.
Hepatocellular carcinoma, or HCC, is one of the leading causes of cancer-related death worldwide, and its molecular landscape has been mapped in increasing detail over the past decade through large-scale sequencing efforts. Among the recurrent alterations identified in human HCC samples, mutations in CTNNB1 and in the TERT promoter stand out for their exceptionally high frequency. CTNNB1 mutations stabilize the β-catenin protein, allowing it to escape degradation, accumulate in the cell nucleus and drive the expression of proliferation-promoting genes. TERT promoter mutations, meanwhile, create binding sites for transcription factors that boost expression of telomerase reverse transcriptase, the enzyme that rebuilds chromosome ends and grants cells the replicative immortality that cancer demands. Despite the well-documented prevalence of both alterations, the functional consequences of their co-occurrence had remained poorly understood, leaving a significant gap in the mechanistic picture of how liver tumors arise.
To begin closing that gap, the research team first turned to publicly available data from The Cancer Genome Atlas, or TCGA, a comprehensive genomic database of human tumors. Their statistical analysis of HCC samples revealed a significant association between mutations in CTNNB1 and mutations in the TERT promoter, with a Fisher’s exact test yielding a P value below 0.01. In practical terms, this means that liver tumors carrying one of these alterations are significantly more likely than chance alone would predict to carry the other as well. Such non-random co-occurrence is a classic signature of cooperating cancer genes: when two alterations appear together more often than expected, it typically suggests that their combined effect confers a selective growth advantage that natural selection within the tumor favors strongly.
Association, however, is not causation. To test whether β-catenin and TERT genuinely cooperate in driving liver cancer, the researchers employed an elegant and rapid animal modeling technique known as hydrodynamic tail vein injection, or HTVI. This method involves injecting plasmid DNA into the bloodstream of mice in a way that delivers the genetic material directly into hepatocytes, the main functional cells of the liver, allowing researchers to express specific oncogenes in liver tissue and monitor tumor development over time. The team constructed plasmids encoding a constitutively active form of β-catenin, called Δ90 β-catenin, which carries a deletion that prevents its degradation, alongside plasmids encoding TERT itself.
The results of these experiments were striking. When Δ90 β-catenin and TERT were coexpressed in mouse livers, the animals developed hepatocellular carcinoma rapidly, with tumors emerging far sooner and more abundantly than in any of the control conditions. In contrast, expression of Δ90 β-catenin alone produced only minimal tumor formation, and expression of TERT alone produced essentially no tumors at all. This pattern is the hallmark of oncogenic synergy: neither alteration is sufficient on its own to transform liver tissue, but together they unleash a potent cancer-driving program. The finding provides a functional explanation for the genetic co-occurrence observed in human patient data, and it suggests that the two mutations are not merely passengers traveling together but active collaborators in hepatocarcinogenesis.
With the synergy established, the researchers turned their attention to the molecular mechanism underlying it. Using immunohistochemistry, a technique that detects specific proteins in tissue sections, they examined the tumors induced by combined β-catenin and TERT expression and looked for signs of activated signaling cascades. What they found was strong phosphorylation of ERK1/2, the terminal kinases of the MAPK/ERK pathway, a central signaling cascade that transmits growth-promoting signals from the cell surface to the nucleus. ERK1/2 phosphorylation is a well-established readout of MAPK/ERK pathway activation, and its robust presence in the β-catenin and TERT-driven tumors indicated that this pathway had been switched on in the tumor cells.
To determine whether this pathway activation was merely a byproduct of tumorigenesis or an essential driver of it, the researchers performed a genetic knockdown experiment targeting MEK1/2, the upstream kinases responsible for phosphorylating ERK1/2. When MEK1/2 expression was suppressed in the mouse livers receiving the β-catenin and TERT plasmids, tumor formation was markedly reduced. This loss-of-function experiment confirmed that MAPK/ERK signaling is not incidental but indispensable for the oncogenic cooperation between β-catenin and TERT. In other words, without the MAPK/ERK cascade, the two cancer genes lose their combined power to transform liver tissue, identifying the pathway as a critical dependency of this tumor subtype.
The clinical implications of these findings are considerable. The MAPK/ERK pathway is already a major focus of drug development across many cancer types, and a range of inhibitors targeting components of the cascade, including MEK inhibitors, have been developed and tested clinically. The new study suggests that patients whose liver tumors harbor both CTNNB1 and TERT promoter mutations may represent a molecular subtype that is particularly dependent on MAPK/ERK signaling, and therefore potentially responsive to therapies that target this cascade. Genomic testing for the co-occurrence of these two mutations could, in principle, help identify patients most likely to benefit from such an approach, although the researchers emphasize that their work is preclinical and that translating the findings into patient treatment will require further study.
Beyond its therapeutic implications, the study fills an important conceptual void in liver cancer biology. β-catenin is classically understood as a transcriptional co-activator in the Wnt signaling pathway, and TERT as a guardian of chromosome integrity, so the demonstration that their cooperation routes through MAPK/ERK activation reveals an unexpected layer of crosstalk between these canonical systems. The work was supported by grants from the National Research Foundation of Korea and approved by the Animal Policy and Welfare Committee of Kyung Hee University. As sequencing of liver tumors becomes increasingly routine in clinical practice, mechanistic studies like this one, which connect specific mutation combinations to druggable signaling dependencies, will become ever more essential to realizing the promise of precision oncology in hepatocellular carcinoma.
Subject of Research: Cooperation between TERT promoter mutations and β-catenin activation in hepatocellular carcinoma development via MAPK/ERK signaling
Article Title: Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation
Article References: Park, H., Lee, J., Moon, H., & Ro, S. W. (2026). Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation. Cancer Cell International. https://doi.org/10.1186/s12935-026-04329-9
Image Credits: AI Generated
DOI: 10.1186/s12935-026-04329-9
Keywords: TERT promoter, β-catenin, hepatocellular carcinoma, MAPK/ERK pathway, liver cancer, telomerase, CTNNB1, oncogenic synergy, hydrodynamic tail vein injection, ERK1/2 phosphorylation, MEK1/2, cancer genetics
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Nathaniel Bowman. (September 21, 2026). Telomerase and β-Catenin Join Forces to Drive Aggressive Liver Cancer. Scienmag. https://scienmag.com/telomerase-and-%ce%b2-catenin-join-forces-to-drive-aggressive-liver-cancer/
Nathaniel Bowman. “Telomerase and β-Catenin Join Forces to Drive Aggressive Liver Cancer.” Scienmag, 21 September 2026, https://scienmag.com/telomerase-and-%ce%b2-catenin-join-forces-to-drive-aggressive-liver-cancer/. Accessed 21 September 2026.
Nathaniel Bowman. “Telomerase and β-Catenin Join Forces to Drive Aggressive Liver Cancer.” Scienmag. September 21, 2026. https://scienmag.com/telomerase-and-%ce%b2-catenin-join-forces-to-drive-aggressive-liver-cancer/
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Tags: Cancer GeneticsCTNNB1CTNNB1 gene mutations in liver cancerERK1/2 phosphorylationgenetic cooperation in liver cancer developmenthepatocellular carcinomahepatocellular carcinoma molecular landscapehydrodynamic tail vein injectionimplications of β-catenin and telomerase activationliver cancerliver cancer geneticsliver cancer mutation analysisMAPK/ERK pathwayMEK1/2molecular mechanisms of aggressive liver canceroncogenic synergyrole of MAPK/ERK pathway in liver cancer progressiontargeted therapy for hepatocellular carcinomatelomerasetelomerase and β-catenin in hepatocellular carcinomaTERT promoterTERT promoter mutations in HCCtherapeutic targets in liverβ-catenin
