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PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis.

Gao F, Wang X, Zhu F, Wang Q, Zhang X, Guo C, Zhou C, Ma C, Sun W, Zhang Y, Chen YH, Zhang L - J. Cell. Mol. Med. (2009)

Bottom Line: Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas.Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity.These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.

ABSTRACT
Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5'CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5'CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (gamma=-1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5'CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.

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Prognostic value of PDCD4 expression for patients with gliomas. The survival times of 51 patients with high-grade gliomas were analysed using the Kaplan–Meier method. The difference in survival time between patients with PDCD4+ gliomas and patients with PDCD4– gliomas is statistically significant (P < 0.05) as determined by the log-rank test.
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fig05: Prognostic value of PDCD4 expression for patients with gliomas. The survival times of 51 patients with high-grade gliomas were analysed using the Kaplan–Meier method. The difference in survival time between patients with PDCD4+ gliomas and patients with PDCD4– gliomas is statistically significant (P < 0.05) as determined by the log-rank test.

Mentions: Furthermore, to assess the association of PDCD4 expression with patient survival, the survival data from 84 patients with gliomas (33 low grade and 51 high grade) were generated by a 3-year follow-up. We analysed the relationship between PDCD4 expression at protein level and clinicopathological characteristics in primary gliomas. The results showed that no significant correlation between PDCD4 expression and age, histological type or pathological grade existed (Table 1). The expression of PDCD4 was neither significantly associated with the survival rate of patients with a low grade of gliomas (n= 33) (data not shown). However, among 51 patients with high-grade gliomas, the expression of PDCD4 significantly correlated with the long-term survival rate of patients. The survival rate of patients with PDCD4-expressing gliomas was significantly higher than that of patients with PDCD4– gliomas (P= 0.0013) (Fig. 5). To examine whether the PDCD4 silencing was an independent unfavourable prognostic factor for patients, we performed a multivariant Cox regression analysis, including gender, age, histological types, grade and PDCD4 expression (Supporting Table S1). The level of PDCD4 expression could significantly predict the patient outcome independent of other clinicopathological variables for disease-specific survival (relative risk, 0.063; 95% confidence interval, 0.014–0.276, P < 0.0001). Thus, PDCD4 expression in primary gliomas can serve as an important factor for prognosis of high-grade gliomas. In addition, there appeared to be a tendency for PDCD4 expression to be associated with gender (see Table 1). The expression of PDCD4 in gliomas from male patients was significantly higher than that from female patients (P= 0.0245).


PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis.

Gao F, Wang X, Zhu F, Wang Q, Zhang X, Guo C, Zhou C, Ma C, Sun W, Zhang Y, Chen YH, Zhang L - J. Cell. Mol. Med. (2009)

Prognostic value of PDCD4 expression for patients with gliomas. The survival times of 51 patients with high-grade gliomas were analysed using the Kaplan–Meier method. The difference in survival time between patients with PDCD4+ gliomas and patients with PDCD4– gliomas is statistically significant (P < 0.05) as determined by the log-rank test.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496131&req=5

fig05: Prognostic value of PDCD4 expression for patients with gliomas. The survival times of 51 patients with high-grade gliomas were analysed using the Kaplan–Meier method. The difference in survival time between patients with PDCD4+ gliomas and patients with PDCD4– gliomas is statistically significant (P < 0.05) as determined by the log-rank test.
Mentions: Furthermore, to assess the association of PDCD4 expression with patient survival, the survival data from 84 patients with gliomas (33 low grade and 51 high grade) were generated by a 3-year follow-up. We analysed the relationship between PDCD4 expression at protein level and clinicopathological characteristics in primary gliomas. The results showed that no significant correlation between PDCD4 expression and age, histological type or pathological grade existed (Table 1). The expression of PDCD4 was neither significantly associated with the survival rate of patients with a low grade of gliomas (n= 33) (data not shown). However, among 51 patients with high-grade gliomas, the expression of PDCD4 significantly correlated with the long-term survival rate of patients. The survival rate of patients with PDCD4-expressing gliomas was significantly higher than that of patients with PDCD4– gliomas (P= 0.0013) (Fig. 5). To examine whether the PDCD4 silencing was an independent unfavourable prognostic factor for patients, we performed a multivariant Cox regression analysis, including gender, age, histological types, grade and PDCD4 expression (Supporting Table S1). The level of PDCD4 expression could significantly predict the patient outcome independent of other clinicopathological variables for disease-specific survival (relative risk, 0.063; 95% confidence interval, 0.014–0.276, P < 0.0001). Thus, PDCD4 expression in primary gliomas can serve as an important factor for prognosis of high-grade gliomas. In addition, there appeared to be a tendency for PDCD4 expression to be associated with gender (see Table 1). The expression of PDCD4 in gliomas from male patients was significantly higher than that from female patients (P= 0.0245).

Bottom Line: Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas.Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity.These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.

ABSTRACT
Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5'CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5'CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (gamma=-1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5'CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.

Show MeSH
Related in: MedlinePlus