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hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness

Oncogene volume 34, pages 3402–3412 (2015)Cite this article

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Abstract

Stress hormones have been implicated in both tumor initiation and progression. Human telomerase reverse transcriptase (hTERT) is overexpressed in cancer cells and associated with malignant tumor progression and poor outcome. We thus sought to determine whether the stress hormone norepinephrine (NE) could induce hTERT expression and subsequently ovarian cancer progression. Unexpectedly, NE induced hTERT transcript and protein expression, and subsequently ovarian cancer cell invasion. Pharmacologic inhibition of β2-adrenergic receptor 2 and protein kinase A, as well as silencing of hypoxia-inducible factor-1α and c-Myc expression, profoundly attenuated NE-induced hTERT expression. Strikingly, stimulation of the cells with NE or ectopic expression of hTERT induced expression of Slug, ovarian cancer cell epithelial–mesenchymal transition (EMT) and invasion. Silencing of hTERT expression abrogated NE-induced ovarian cancer cell invasion, EMT and Slug expression. In addition, silencing of Slug expression significantly inhibited NE- and hTERT-induced ovarian cancer cell EMT and invasion. Moreover, continuous exposure to NE was sufficient to enhance in vivo hTERT expression and metastasis of ovarian cancer cells to the lung. Finally, we provide evidence that hTERT links Src to Slug expression in NE-induced ovarian cancer EMT and metastasis. We thus demonstrate a novel role of hTERT in stress hormone-induced ovarian cancer aggressiveness through inducing Slug, providing novel biomarkers and potential therapeutic targets for ovarian cancer.

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Acknowledgements

We thank Professor Bong-Kyeong Oh (KonKuk University, Seoul, South Korea) for a plasmid-containing hTERT, Sun Hee Leem (Dong-A University, Pusan, Korea) for hTERT promoter and Seong-Lan Yu for experimental support. This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (121182) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0015761, 2013R1A1A2A10059565).

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  1. M J Choi and K H Cho: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea

    M J Choi, K H Cho, Y J Bae & H Y Lee

  2. Department of Biochemistry, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea

    S Lee & J H Park

  3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K J Jeong, J-S Lee & G B Mills

  4. Yonsei Cancer Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    S Y Rha & H Y Lee

  5. Department of Optometry, College of Medical Science, Konyang University, Daejeon, Korea

    E J Choi

  6. Cancer Research Institute, Regional Cancer Center and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea

    J M Kim

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Choi, M., Cho, K., Lee, S. et al. hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness. Oncogene 34, 3402–3412 (2015). https://doi.org/10.1038/onc.2014.270

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