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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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Related in: MedlinePlus

Kaplan-Meier survival analysis of TIMELESS expression using the GOBO online tool, which comprises of pooled data from 1881 breast cancer cases from 11 public data sets. Samples were stratified into tertiles based on TIMELESS expression level. The log-rank test was performed in all tumor samples as well as in different tumor subtypes using distant metastasis-free survival (DMFS) as the endpoint. High TIMELESS expression is significantly associated with lower DMFS over time among (A) all cases regardless of tumor ER- and LN-positivity (P = 1.65E-3), (B) cases with ER-positive tumors (P = 2.20E-4), (C) cases with LN-negative tumors (P = 9.00E-5), and (D) cases with ER-positive and LN-negative tumors (P = 1.00E-5).
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Figure 2: Kaplan-Meier survival analysis of TIMELESS expression using the GOBO online tool, which comprises of pooled data from 1881 breast cancer cases from 11 public data sets. Samples were stratified into tertiles based on TIMELESS expression level. The log-rank test was performed in all tumor samples as well as in different tumor subtypes using distant metastasis-free survival (DMFS) as the endpoint. High TIMELESS expression is significantly associated with lower DMFS over time among (A) all cases regardless of tumor ER- and LN-positivity (P = 1.65E-3), (B) cases with ER-positive tumors (P = 2.20E-4), (C) cases with LN-negative tumors (P = 9.00E-5), and (D) cases with ER-positive and LN-negative tumors (P = 1.00E-5).

Mentions: Analyzing the lymph node-negative breast cancer data set of GSE2034, we found that patients with lower TIMELESS expression levels were more likely to have a higher rate of distant metastasis-free survival (DMFS) (P < 0.05). Interrogating TIMELESS expression using the GOBO database revealed similar results: increased TIMELESS expression was associated with lower DMFS rate not only in the general breast tumor population (P < 0.005), but also in tumor subtypes, including lymph node-negative (P < 0.001), ER-positive (P < 0.001), and lymph node- negative ER-positive (P < 0.001) breast tumors (Figure 2).


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)

Kaplan-Meier survival analysis of TIMELESS expression using the GOBO online tool, which comprises of pooled data from 1881 breast cancer cases from 11 public data sets. Samples were stratified into tertiles based on TIMELESS expression level. The log-rank test was performed in all tumor samples as well as in different tumor subtypes using distant metastasis-free survival (DMFS) as the endpoint. High TIMELESS expression is significantly associated with lower DMFS over time among (A) all cases regardless of tumor ER- and LN-positivity (P = 1.65E-3), (B) cases with ER-positive tumors (P = 2.20E-4), (C) cases with LN-negative tumors (P = 9.00E-5), and (D) cases with ER-positive and LN-negative tumors (P = 1.00E-5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Kaplan-Meier survival analysis of TIMELESS expression using the GOBO online tool, which comprises of pooled data from 1881 breast cancer cases from 11 public data sets. Samples were stratified into tertiles based on TIMELESS expression level. The log-rank test was performed in all tumor samples as well as in different tumor subtypes using distant metastasis-free survival (DMFS) as the endpoint. High TIMELESS expression is significantly associated with lower DMFS over time among (A) all cases regardless of tumor ER- and LN-positivity (P = 1.65E-3), (B) cases with ER-positive tumors (P = 2.20E-4), (C) cases with LN-negative tumors (P = 9.00E-5), and (D) cases with ER-positive and LN-negative tumors (P = 1.00E-5).
Mentions: Analyzing the lymph node-negative breast cancer data set of GSE2034, we found that patients with lower TIMELESS expression levels were more likely to have a higher rate of distant metastasis-free survival (DMFS) (P < 0.05). Interrogating TIMELESS expression using the GOBO database revealed similar results: increased TIMELESS expression was associated with lower DMFS rate not only in the general breast tumor population (P < 0.005), but also in tumor subtypes, including lymph node-negative (P < 0.001), ER-positive (P < 0.001), and lymph node- negative ER-positive (P < 0.001) breast tumors (Figure 2).

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