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Cancer Lett. 2017 Aug 28;402:117-130. doi: 10.1016/j.canlet.2017.05.022. Epub 2017 Jun 3.

TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway and promoting the epithelial mesenchymal transition.

Author information

1
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, China. Electronic address: liusl@sysucc.org.cn.
2
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Radiotherapy, Sun Yat-sen University Cancer Center, China. Electronic address: linhx@sysucc.org.cn.
3
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China. Electronic address: linchy@sysucc.org.cn.
4
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Radiotherapy, Sun Yat-sen University Cancer Center, China. Electronic address: sunxq@sysucc.org.cn.
5
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China. Electronic address: yelp@sysucc.org.cn.
6
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, China. Electronic address: qiufang@sysucc.org.cn.
7
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, China. Electronic address: wenwen@sysucc.org.cn.
8
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Radiotherapy, Sun Yat-sen University Cancer Center, China. Electronic address: huaxin@sysucc.org.cn.
9
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China. Electronic address: wuxianq@sysucc.org.cn.
10
Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, China. Electronic address: lijun37@mail.sysu.edu.cn.
11
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China. Electronic address: songlb@sysucc.org.cn.
12
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China; Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, China. Electronic address: guoling@sysucc.org.cn.

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.

KEYWORDS:

Apoptosis; Cisplatin; Epithelial–mesenchymal transition; Nasopharyngeal carcinoma; TIMELESS; Wnt/β-catenin pathway

PMID:
28583847
DOI:
10.1016/j.canlet.2017.05.022
[Indexed for MEDLINE]

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