Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells
Abstract
Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-β1 and β-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with β-catenin, enhances its nuclear localization and transcriptional activity, and occupies the β-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.
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Apart from initiating replicative immortality, telomerase seems to play a crucial role in almost all the hallmarks of cancer, including cell growth and proliferation through activation of EGFR signaling, resistance to apoptosis through activation of NF-kB, promotion of invasion and metastasis through induction of epithelial-mesenchymal transition via the Wnt/b-catenin pathway that upregulates Snai
“It has to be noted though that apart from initiating replicative immortality, telomerase seems to play a crucial role in almost all the hallmarks of cancer, ranging from cell growth and proliferation through to the activation of EGFR signaling [182], resistance to apoptosis through activation of NF-kB [183], and the promotion of invasion and metastasis through induction of the epithelial–mesenchym”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [184]
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- Authors
- Liu, Z., Li, Q., Li, K., Chen, L., Li, W., Hou, M., Liu, T., Yang, J., Lindvall, C., Björkholm, M., Jia, J., & Xu, D.
- Affiliations
- Shandong University (CN)
- Karolinska University Hospital (SE)
- Van Andel Institute (US)
- Corresponding author
- Jia, J
- Venue
- Oncogene
- Published
- 2012-10-08
- Volume
- 32
- Issue
- 36
- Pages
- 4203-4213
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2042897772
- Cited by
- 276
- References
- 55
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 8 · 2023: 22 · 2022: 23 · 2021: 22 · 2020: 31 · 2019: 19 · 2018: 19 · 2017: 22 · 2016: 24 · 2015: 25 · 2014: 21 · 2013: 19
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Prevent Cancer Foundation
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- telomerase reverse transcriptase, hTERT, epithelial-mesenchymal transition, cancer stem cells, gastric cancer, β-catenin, TGF-β1, metastasis, tumor recurrence, telomere maintenance
- MeSH terms
- Snail Family Transcription Factors, Animals, Catalysis, Cell Nucleus, Cell Transformation, Neoplastic, Humans, Neoplasm Invasiveness, Neoplasms, Promoter Regions, Genetic, Protein Binding, Stomach Neoplasms, Transcription Factors, Transcription, Genetic, Neoplastic Stem Cells, Vimentin, Signal Transduction, Biomarkers, Gene Expression, Gene Expression Regulation, Neoplastic, Hyaluronan Receptors, Telomerase, Protein Transport, RNA Interference, Quantitative Trait Loci, Cell Line, Tumor, beta Catenin, Mice, Transforming Growth Factor beta1, Epithelial-Mesenchymal Transition
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