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Open Access Highly Accessed Research article

Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses

Yingying Mao12, Alan Fu2, Derek Leaderer2, Tongzhang Zheng2, Kun Chen1 and Yong Zhu2*

Author Affiliations

1 Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou, Zhejiang Province, China

2 Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA

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BMC Cancer 2013, 13:498  doi:10.1186/1471-2407-13-498

Published: 25 October 2013

Abstract

Background

The circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems.

Methods

To assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS-targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis.

Results

TIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate.

Conclusions

Our results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome.

Keywords:
TIMELESS; Circadian gene; Cell cycle; Tumorigenesis; Expression profiling