title: Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses.
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.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Mao
authors.forename: Alan
authors.initials: A
authors.lastname: Fu
authors.forename: Derek
authors.initials: D
authors.lastname: Leaderer
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA. yong.zhu@yale.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C509769:TIMELESS protein, human