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TERT drives liver tumorigenesis and immune reprogramming independently of telomere elongation

ABSTRACT: We generated two mouse models, p21⁺/Tert and p21⁺/TertCi, that express either telomerase reverse transcriptase (TERT) or its catalytically inactive form under the control of the p21 promoter, establishing a feedback loop that restricts telomerase expression to p21-positive cells. By 18–20 months of age, approximately 15% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing revealed activating mutations in Ctnnb1 in p21⁺/Tert tumors, and activating HrasGln61Lys mutations in p21⁺/TertCi tumors, associated with elevated C>A transversions as well as recurrent PP1 subunit mutations in multiple tumors. Despite distinct point mutations, both models exhibited chromosomal alterations recurrent in human HCC. β-catenin–activated tumors displayed gene expression signatures characteristic of human HCC, as well as SLC1A5 overexpression, whereas MAPK-mutated tumors showed transcriptional profiles consistent with MAPK/ERK pathway activation. Both genotypes demonstrated upregulation of glycolytic enzymes and downregulation of gluconeogenic enzymes such as FBP1, but overexpressed distinct NRF2 targets. Spatial architecture of the tumors using the Hyperion™ Imaging System revealed reduced HNF4A-positive hepatocytes in all tumors, independent of Hnf4a transcriptional changes, and markedly decreased immune cell infiltration in β-catenin–activated tumors. Together, these results uncover unanticipated roles for TERT beyond telomere elongation and identify molecular and metabolic biomarkers predictive of immunotherapy response in HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE317255 | GEO | 2026/06/29

REPOSITORIES: GEO

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Telomerase upregulation induces progression of mouse BrafV600E-driven thyroid cancers and triggers non-telomeric effects

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Detection of novel fusion transcriptVTI1A-CFAP46 in HHC by RNA-seq

Project description:HCC is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways, such as: Wnt/β-Catenin, p53, telomerase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been explored in HCC. To identify novel fusion transcript in HCC, in the first phase of our study, we performed targeted RNA sequencing on 6 patients with the diagnosis of HCC who underwent liver transplant (from HCC and paired non-HCC tissues). As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of the study, we measured the expression of wild-type VTI1A in total of 21 HCC specimens (additional 13 patients) showing that 10 of 21 had up-regulation of wild-type VTI1A. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE), which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC. The link between this alteration and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.

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2015-01-03 | E-GEOD-63863 | biostudies-arrayexpress

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2012-01-17 | E-GEOD-35045 | biostudies-arrayexpress

Promoter hypermethylation of TERT is associated with hepatocellular carcinoma in the Han Chinese population

2015-01-03 | GSE63863 | GEO

TERT Promoter Mutations Combined with TP53 Mutations as Potential Biomarkers for Hepatocellular Carcinoma Recurrence and Prognosis

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2012-01-17 | E-GEOD-35046 | biostudies-arrayexpress

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