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Telomerase reverse transcriptase promotes epithelial–mesenchymal transition and stem cell-like traits in cancer cells

Oncogene volume 32, pages 4203–4213 (2013)Cite this article

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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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Acknowledgements

We thank Drs RA Weinberg (Massachusetts Institute of Technology), CM Counter (Duke University), JM Wong and K Collins (University of California, Berkeley), Y Cong (Beijing Normal University) and W Cui (Imperial College London) for retroviral vectors and plasmids.This study was supported by the National Basic Research Program of China (grant No. 973 Program 2012CB911202), the Swedish Cancer Society, the Swedish Research Council, Cancer Society in Stockholm, Swedish Child Cancer Society, the Karolinska Institutet Foundations, National Natural Science Foundation of China (No.: 30770118, 30800406, 30972775, 81071721, 81000868, 81171536), the National Key Scientific Program of China (2007CB914801) and the Science Foundation of Shandong Province (No.: ZR2009CZ001, ZR2009CM002 and BS2010YY040)

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Authors and Affiliations

  1. Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine and Second Hospital, Shandong University, Jinan, PR China

    Z Liu, Q Li, L Chen, W Li & J Jia

  2. Department of Medicine, Division of Haematology and Centre for Molecular Medicine (CMM), Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    Z Liu, Q Li, T Liu, J Yang, M Björkholm & D Xu

  3. Department of Biosciences and Nutrition, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    K Li

  4. Department of Women and Child Health, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    M Hou

  5. Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI, USA

    C Lindvall

  6. Central Research Laboratory, the Second Hospital of Shandong University, , Jinan, PR China

    D Xu

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Liu, Z., Li, Q., Li, K. et al. Telomerase reverse transcriptase promotes epithelial–mesenchymal transition and stem cell-like traits in cancer cells. Oncogene 32, 4203–4213 (2013). https://doi.org/10.1038/onc.2012.441

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  • DOI: https://doi.org/10.1038/onc.2012.441

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