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

Mao Y, Fu A, Leaderer D, Zheng T, Chen K, Zhu Y - BMC Cancer (2013)

Bottom Line: 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.Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA. yong.zhu@yale.edu.

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.

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MCF7 and HeLa cell proliferation rates were assessed at baseline, 24 hours, 48 hours, 72 hours, and 96 hours following transfection with a TIMELESS siRNA and a scrambled sequence negative control oligo. (A) Transfection with TIMELESS siRNA in MCF7 cells slowed down cell proliferation compared to negative controls (P < 0.05); (B)TIMELESS knockdown did not result in a significant reduction in cell proliferation rate in HeLa cells. Error bars represent standard deviations.
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Figure 4: MCF7 and HeLa cell proliferation rates were assessed at baseline, 24 hours, 48 hours, 72 hours, and 96 hours following transfection with a TIMELESS siRNA and a scrambled sequence negative control oligo. (A) Transfection with TIMELESS siRNA in MCF7 cells slowed down cell proliferation compared to negative controls (P < 0.05); (B)TIMELESS knockdown did not result in a significant reduction in cell proliferation rate in HeLa cells. Error bars represent standard deviations.

Mentions: As suggested by the findings of our network analysis, we tested TIMELESS’s potential role in cellular growth and proliferation using a MTS assay. As shown in Figure 4, transfection with TIMELESS-targeting siRNA oligos significantly decreased MCF7 cell growth compared to untreated MCF7 cells (P < 0.05) and negative control cells (P < 0.05). A similar trend was observed with HeLa cells, but only a slight, yet not statistically significant, decrease in proliferation rate was observed compared to negative control cells (P = 0.156).


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

Mao Y, Fu A, Leaderer D, Zheng T, Chen K, Zhu Y - BMC Cancer (2013)

MCF7 and HeLa cell proliferation rates were assessed at baseline, 24 hours, 48 hours, 72 hours, and 96 hours following transfection with a TIMELESS siRNA and a scrambled sequence negative control oligo. (A) Transfection with TIMELESS siRNA in MCF7 cells slowed down cell proliferation compared to negative controls (P < 0.05); (B)TIMELESS knockdown did not result in a significant reduction in cell proliferation rate in HeLa cells. Error bars represent standard deviations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924353&req=5

Figure 4: MCF7 and HeLa cell proliferation rates were assessed at baseline, 24 hours, 48 hours, 72 hours, and 96 hours following transfection with a TIMELESS siRNA and a scrambled sequence negative control oligo. (A) Transfection with TIMELESS siRNA in MCF7 cells slowed down cell proliferation compared to negative controls (P < 0.05); (B)TIMELESS knockdown did not result in a significant reduction in cell proliferation rate in HeLa cells. Error bars represent standard deviations.
Mentions: As suggested by the findings of our network analysis, we tested TIMELESS’s potential role in cellular growth and proliferation using a MTS assay. As shown in Figure 4, transfection with TIMELESS-targeting siRNA oligos significantly decreased MCF7 cell growth compared to untreated MCF7 cells (P < 0.05) and negative control cells (P < 0.05). A similar trend was observed with HeLa cells, but only a slight, yet not statistically significant, decrease in proliferation rate was observed compared to negative control cells (P = 0.156).

Bottom Line: 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.Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA. yong.zhu@yale.edu.

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.

Show MeSH
Related in: MedlinePlus