1. TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway and promoting the epithelial mesenchymal transition.
- Author
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Liu SL, Lin HX, Lin CY, Sun XQ, Ye LP, Qiu F, Wen W, Hua X, Wu XQ, Li J, Song LB, and Guo L
- Subjects
- Adult, Animals, Biomarkers, Tumor genetics, Carcinoma genetics, Carcinoma metabolism, Carcinoma pathology, Cell Cycle Proteins genetics, Cell Line, Tumor, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins genetics, Kaplan-Meier Estimate, Male, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Nasopharyngeal Carcinoma, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms metabolism, Nasopharyngeal Neoplasms pathology, Neoplasm Grading, Neoplasm Staging, Phenotype, Proportional Hazards Models, RNA Interference, Time Factors, Transcription, Genetic, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Apoptosis drug effects, Biomarkers, Tumor metabolism, Carcinoma drug therapy, Cell Cycle Proteins metabolism, Cisplatin pharmacology, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition drug effects, Intracellular Signaling Peptides and Proteins metabolism, Nasopharyngeal Neoplasms drug therapy, Wnt Signaling Pathway drug effects
- Abstract
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/β-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., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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