Choi M J, Cho K H, Lee S, Bae Y J, Jeong K J, Rha S Y, Choi E J, Park J H, Kim J M, Lee J-S, Mills G B, Lee H Y
Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
Department of Biochemistry, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
Oncogene. 2015 Jun;34(26):3402-12. doi: 10.1038/onc.2014.270. Epub 2014 Aug 25.
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.
应激激素与肿瘤的起始和进展均有关联。人端粒酶逆转录酶（hTERT）在癌细胞中过度表达，并与恶性肿瘤进展及不良预后相关。因此，我们试图确定应激激素去甲肾上腺素（NE）是否能诱导hTERT表达，进而促进卵巢癌进展。出乎意料的是，NE诱导了hTERT转录本和蛋白表达，随后促进了卵巢癌细胞的侵袭。对β2 - 肾上腺素能受体2和蛋白激酶A的药理抑制，以及缺氧诱导因子-1α和c-Myc表达的沉默，显著减弱了NE诱导的hTERT表达。引人注目的是，用NE刺激细胞或hTERT的异位表达诱导了Slug的表达、卵巢癌细胞上皮-间质转化（EMT）和侵袭。hTERT表达的沉默消除了NE诱导的卵巢癌细胞侵袭、EMT和Slug表达。此外，Slug表达的沉默显著抑制了NE和hTERT诱导的卵巢癌细胞EMT和侵袭。而且，持续暴露于NE足以增强体内hTERT表达以及卵巢癌细胞向肺的转移。最后，我们提供证据表明，在NE诱导的卵巢癌EMT和转移过程中，hTERT将Src与Slug表达联系起来。因此，我们证明了hTERT通过诱导Slug在应激激素诱导的卵巢癌侵袭性中发挥新作用，为卵巢癌提供了新的生物标志物和潜在治疗靶点。
