Journal
CANCER LETTERS
Volume 402, Issue -, Pages 117-130Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.05.022
Keywords
Apoptosis; Cisplatin; Epithelial-mesenchymal transition; Nasopharyngeal carcinoma; TIMELESS; Wnt/beta-catenin pathway
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Funding
- National Natural Science Foundation of China [81572848, 81530082, 81372814, 81325013, 91529301]
- Sci-Tech Project Foundation of Guangdong Province, China [2012B031800255, 2014A020212528]
- Guangzhou Science and Technology Planning Project, China [2014J4100181]
- Science and Technology Department of Guangdong Province, China [2014A030313220, 201 6A030308002, 2014A030313008]
- Science and Technology Program of Guangzhou, China [15020077]
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This study investigated the expression, clinicopathological significance and mechanism of action of TIMELESS, a mammalian homolog of a Drosophila circadian rhythm gene, in nasopharyngeal carcinoma. Quantitative real-time PCR, western blotting and immunohistochemistry revealed TIMELESS was upregulated in NPC cell lines (n = 8 vs. NP69 cells), and freshly-frozen (n = 6) and paraffin-embedded human NPC specimens (n = 108 vs. normal samples/non-tumor cells). TIMELESS expression was associated with T category (P = 0.002), N category (P = 0.001), clinical stage (P < 0.001), metastasis (P = 0.047), vital status (P = 0.013) and serum Epstein-Barr DNA (P = 0.005). High TIMELESS expression was associated with poorer overall survival (80.7% vs. 95.9%; P = 0.004) and progression free survival (68.1% vs. 88.0%; P = 0.005). Univariate and multivariate analysis revealed TIMELESS was an independent prognostic factor for overall survival and progression free survival. Stable ectopic overexpression of TIMELESS in NPC cell lines conferred resistance to cisplatin-induced apoptosis in vitro and in vivo, promoted an epithelial-to-mesenchymal transition phenotype, and activated the Wnt/beta-catenin pathway and downstream gene transcription; knockdown of TIMELESS had the opposite effects. TIMELESS may play a role in the development of NPC and could represent a valuable prognostic factor and potential therapeutic target. (C) 2017 Elsevier B.V. All rights reserved.
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