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OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice.

Yang YR, Jang HJ, Yoon S, Lee YH, Nam D, Kim IS, Lee H, Kim H, Choi JH, Kang BH, Ryu SH, Suh PG - Oncogenesis (2014)

Bottom Line: In two independent microarray data sets, the expression of OGA and OGT was significantly associated with poor cancer-specific survival of colorectal cancer (CRC) patients.Apc(min/+) OGA(+/-) mice exhibited a significantly increased survival rate compared with Apc(min/+) mice.However, the knockout of OGA did not affect Wnt/β-catenin signaling.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

ABSTRACT
Emerging evidence suggests that aberrant O-GlcNAcylation is associated with tumorigenesis. Many oncogenic factors are O-GlcNAcylated, which modulates their functions. However, it remains unclear how O-GlcNAcylation and O-GlcNAc cycling enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), affect the development of cancer in animal models. In this study, we show that reduced level of OGA attenuates colorectal tumorigenesis induced by Adenomatous polyposis coli (Apc) mutation. The levels of O-GlcNAcylation and O-GlcNAc cycling enzymes were simultaneously upregulated in intestinal adenomas from mice, and in human patients. In two independent microarray data sets, the expression of OGA and OGT was significantly associated with poor cancer-specific survival of colorectal cancer (CRC) patients. In addition, OGA heterozygosity, which results in increased levels of O-GlcNAcylation, attenuated intestinal tumor formation in the Apc(min/+) background. Apc(min/+) OGA(+/-) mice exhibited a significantly increased survival rate compared with Apc(min/+) mice. Consistent with this, Apc(min/+) OGA(+/-) mice expressed lower levels of Wnt target genes than Apc(min/+). However, the knockout of OGA did not affect Wnt/β-catenin signaling. Overall, these findings suggest that OGA is crucial for tumor growth in CRC independently of Wnt/β-catenin signaling.

No MeSH data available.


Related in: MedlinePlus

Association of the expression levels of O-GlcNac cycling enzymes with CRC patient survival and relapse. (a) The MCC cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of disease-specific survival were compared. (b) The Norwegian patient cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of relapse-free survival were compared. The split with the lowest P-value in the log-rank test was selected from among the median 60% of samples sorted by gene expression levels. The hazard ratios and P-values shown in the plots were calculated from Cox's proportional-hazard regression model.
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fig2: Association of the expression levels of O-GlcNac cycling enzymes with CRC patient survival and relapse. (a) The MCC cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of disease-specific survival were compared. (b) The Norwegian patient cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of relapse-free survival were compared. The split with the lowest P-value in the log-rank test was selected from among the median 60% of samples sorted by gene expression levels. The hazard ratios and P-values shown in the plots were calculated from Cox's proportional-hazard regression model.

Mentions: Because the aberrant expression of OGT and OGA has been reported in different types of cancer, we assessed whether OGT and OGA expression exhibits prognostic value in CRC. Two independent cohorts of CRC patients from the Moffitt Cancer Center (GSE17536)19 and a Norwegian hospital (Norwegian; GSE30378)20 were analyzed for the association between OGT and OGA expression and patient survival and cancer recurrence. The Moffitt Cancer Center data set reported the disease-specific survival times for 177 CRC patients. The gene expression levels of OGT and OGA had a strong positive correlation (Pearson's correlation=0.71; P-value <2.2e−16), supporting the upregulation of these genes in cancer (Figures 1a and e). Expression was also significantly associated with the disease-specific survival probability: OGT and OGA had hazard ratios of 2.26 (P=0.00245) and 2.42 (P=0.0155). Patients with reduced levels of OGT and OGA exhibited improved survival rates (Figures 2a and b).


OGA heterozygosity suppresses intestinal tumorigenesis in Apc(min/+) mice.

Yang YR, Jang HJ, Yoon S, Lee YH, Nam D, Kim IS, Lee H, Kim H, Choi JH, Kang BH, Ryu SH, Suh PG - Oncogenesis (2014)

Association of the expression levels of O-GlcNac cycling enzymes with CRC patient survival and relapse. (a) The MCC cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of disease-specific survival were compared. (b) The Norwegian patient cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of relapse-free survival were compared. The split with the lowest P-value in the log-rank test was selected from among the median 60% of samples sorted by gene expression levels. The hazard ratios and P-values shown in the plots were calculated from Cox's proportional-hazard regression model.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150210&req=5

fig2: Association of the expression levels of O-GlcNac cycling enzymes with CRC patient survival and relapse. (a) The MCC cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of disease-specific survival were compared. (b) The Norwegian patient cohort was divided into two groups according to O-GlcNac enzyme levels, and the Kaplan–Meier curves of relapse-free survival were compared. The split with the lowest P-value in the log-rank test was selected from among the median 60% of samples sorted by gene expression levels. The hazard ratios and P-values shown in the plots were calculated from Cox's proportional-hazard regression model.
Mentions: Because the aberrant expression of OGT and OGA has been reported in different types of cancer, we assessed whether OGT and OGA expression exhibits prognostic value in CRC. Two independent cohorts of CRC patients from the Moffitt Cancer Center (GSE17536)19 and a Norwegian hospital (Norwegian; GSE30378)20 were analyzed for the association between OGT and OGA expression and patient survival and cancer recurrence. The Moffitt Cancer Center data set reported the disease-specific survival times for 177 CRC patients. The gene expression levels of OGT and OGA had a strong positive correlation (Pearson's correlation=0.71; P-value <2.2e−16), supporting the upregulation of these genes in cancer (Figures 1a and e). Expression was also significantly associated with the disease-specific survival probability: OGT and OGA had hazard ratios of 2.26 (P=0.00245) and 2.42 (P=0.0155). Patients with reduced levels of OGT and OGA exhibited improved survival rates (Figures 2a and b).

Bottom Line: In two independent microarray data sets, the expression of OGA and OGT was significantly associated with poor cancer-specific survival of colorectal cancer (CRC) patients.Apc(min/+) OGA(+/-) mice exhibited a significantly increased survival rate compared with Apc(min/+) mice.However, the knockout of OGA did not affect Wnt/β-catenin signaling.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

ABSTRACT
Emerging evidence suggests that aberrant O-GlcNAcylation is associated with tumorigenesis. Many oncogenic factors are O-GlcNAcylated, which modulates their functions. However, it remains unclear how O-GlcNAcylation and O-GlcNAc cycling enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), affect the development of cancer in animal models. In this study, we show that reduced level of OGA attenuates colorectal tumorigenesis induced by Adenomatous polyposis coli (Apc) mutation. The levels of O-GlcNAcylation and O-GlcNAc cycling enzymes were simultaneously upregulated in intestinal adenomas from mice, and in human patients. In two independent microarray data sets, the expression of OGA and OGT was significantly associated with poor cancer-specific survival of colorectal cancer (CRC) patients. In addition, OGA heterozygosity, which results in increased levels of O-GlcNAcylation, attenuated intestinal tumor formation in the Apc(min/+) background. Apc(min/+) OGA(+/-) mice exhibited a significantly increased survival rate compared with Apc(min/+) mice. Consistent with this, Apc(min/+) OGA(+/-) mice expressed lower levels of Wnt target genes than Apc(min/+). However, the knockout of OGA did not affect Wnt/β-catenin signaling. Overall, these findings suggest that OGA is crucial for tumor growth in CRC independently of Wnt/β-catenin signaling.

No MeSH data available.


Related in: MedlinePlus