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Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma.

Ling ZQ, Ge MH, Lu XX, Han J, Wu YC, Liu X, Zhu X, Hong LL - Oncotarget (2015)

Bottom Line: We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues.This resulted in down-regulation of Ndrg2 mRNA and protein.We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China.

ABSTRACT
N-myc downstream regulated gene 2 (Ndrg2) is a candidate suppressor of cancer metastasis. We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues. This resulted in down-regulation of Ndrg2 mRNA and protein. Ndrg2 promoter methylation was associated with H. pylori infection and worse prognosis of gastric cancer patients, which is an independent prognostic factor for the disease-free survival (DFS). We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression. These findings uncover a previously unrecognized role for H. pylori infection in gastric cancer.

No MeSH data available.


Related in: MedlinePlus

Correlation of Ndrg2 methylation with Ndrg2 expressionCorrelation of Ndrg2 methylation with Ndrg2 mRNA level determined by real-time RT-PCR analysis and Ndrg2 protein expression determined by immunohistochemical analysis in 292 gastric cancer tissues. Ndrg2 methylation scores inversely correlated with Ndrg2 gene expression in both mRNA and protein levels.
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Figure 3: Correlation of Ndrg2 methylation with Ndrg2 expressionCorrelation of Ndrg2 methylation with Ndrg2 mRNA level determined by real-time RT-PCR analysis and Ndrg2 protein expression determined by immunohistochemical analysis in 292 gastric cancer tissues. Ndrg2 methylation scores inversely correlated with Ndrg2 gene expression in both mRNA and protein levels.

Mentions: To confirm the above mRNA results, we subsequently analyzed Ndrg2 protein expression in 292 GCs and their corresponding PCHNTs using immunohistochemical (IHC) assay. Ndrg2 protein was expressed in the cytoplasm and plasma membrane in histological normal gastric epithelial cells (PCHNTs) with a moderate to strong staining intensity (Figure 1 B1). However, gastric cancer tumor cells displayed significantly reduced Nrdg2 protein expression as compared to PCHNT (Figure 1 B2-B3). We also carried out western blot analyses to confirm the above IHC findings in 30 randomly selected matched primary PCHNT and tumor tissue samples. Some representative western blot results are shown in Figure 1 C1. The average bands intensity of Ndrg2 in gastric cancer is significantly lower than that in PCHNT (P<0.05, Figure 1 C2). The protein levels of Ndrg2 determined by IHC in the 292 GC samples correlated well with the mRNA level of Ndrg2 detected by real-time RT-PCR (r=0.714, P=0.000) (Figure 3). We also analyzed the correlation between Ndrg2 IHC results with clinicopathological factors. The data shows that loss of Ndrg2 protein significantly correlated with H. pylori (HP) infection (P=0.000), venous invasion (P=0.011), lymphatic involvement (P=0.003), invasive depth (P=0.000), lymph node metastasis (P=0.000), distant metastasis (P=0.000) and clinical stage (P=0.000) (Table 1). Collectively, these data indicate that the expression of Ndrg2 is significantly reduced at mRNA and protein levels in GC cells, and loss of Ndrg2 expression may associate with tumor progression and metastasis.


Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma.

Ling ZQ, Ge MH, Lu XX, Han J, Wu YC, Liu X, Zhu X, Hong LL - Oncotarget (2015)

Correlation of Ndrg2 methylation with Ndrg2 expressionCorrelation of Ndrg2 methylation with Ndrg2 mRNA level determined by real-time RT-PCR analysis and Ndrg2 protein expression determined by immunohistochemical analysis in 292 gastric cancer tissues. Ndrg2 methylation scores inversely correlated with Ndrg2 gene expression in both mRNA and protein levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480746&req=5

Figure 3: Correlation of Ndrg2 methylation with Ndrg2 expressionCorrelation of Ndrg2 methylation with Ndrg2 mRNA level determined by real-time RT-PCR analysis and Ndrg2 protein expression determined by immunohistochemical analysis in 292 gastric cancer tissues. Ndrg2 methylation scores inversely correlated with Ndrg2 gene expression in both mRNA and protein levels.
Mentions: To confirm the above mRNA results, we subsequently analyzed Ndrg2 protein expression in 292 GCs and their corresponding PCHNTs using immunohistochemical (IHC) assay. Ndrg2 protein was expressed in the cytoplasm and plasma membrane in histological normal gastric epithelial cells (PCHNTs) with a moderate to strong staining intensity (Figure 1 B1). However, gastric cancer tumor cells displayed significantly reduced Nrdg2 protein expression as compared to PCHNT (Figure 1 B2-B3). We also carried out western blot analyses to confirm the above IHC findings in 30 randomly selected matched primary PCHNT and tumor tissue samples. Some representative western blot results are shown in Figure 1 C1. The average bands intensity of Ndrg2 in gastric cancer is significantly lower than that in PCHNT (P<0.05, Figure 1 C2). The protein levels of Ndrg2 determined by IHC in the 292 GC samples correlated well with the mRNA level of Ndrg2 detected by real-time RT-PCR (r=0.714, P=0.000) (Figure 3). We also analyzed the correlation between Ndrg2 IHC results with clinicopathological factors. The data shows that loss of Ndrg2 protein significantly correlated with H. pylori (HP) infection (P=0.000), venous invasion (P=0.011), lymphatic involvement (P=0.003), invasive depth (P=0.000), lymph node metastasis (P=0.000), distant metastasis (P=0.000) and clinical stage (P=0.000) (Table 1). Collectively, these data indicate that the expression of Ndrg2 is significantly reduced at mRNA and protein levels in GC cells, and loss of Ndrg2 expression may associate with tumor progression and metastasis.

Bottom Line: We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues.This resulted in down-regulation of Ndrg2 mRNA and protein.We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China.

ABSTRACT
N-myc downstream regulated gene 2 (Ndrg2) is a candidate suppressor of cancer metastasis. We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues. This resulted in down-regulation of Ndrg2 mRNA and protein. Ndrg2 promoter methylation was associated with H. pylori infection and worse prognosis of gastric cancer patients, which is an independent prognostic factor for the disease-free survival (DFS). We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression. These findings uncover a previously unrecognized role for H. pylori infection in gastric cancer.

No MeSH data available.


Related in: MedlinePlus