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NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients.

Chu D, Zhang Z, Zhou Y, Li Y, Zhu S, Zhang J, Zhao Q, Ji G, Wang W, Zheng J - Oncotarget (2015)

Bottom Line: Significant negative correlations were found between NDRG4 staining and p-AKT.In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival.It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

ABSTRACT
The role of NDRG4 in human malignancies is largely unknown. We investigated the role of NDRG4 protein in colorectal cancer and its prognostic value in a hospital-based retrospective training cohort of 272 patients and a prospective validation cohort of 708 patients were. Cell line was transfected with an NDRG4 expression construct to confirm the suppression of PI3K-AKT activity by NDRG4. Appropriate statistical methods were utilized for analysis. Results showed that NDRG4 protein expression was significantly decreased from normal mucosa, chronic colitis, ulcerative colitis, atypical hyperplasia to colorectal cancer. Significant negative correlations were found between NDRG4 staining and p-AKT. Patients with positive NDRG4 staining had favorable survival in both study cohorts. In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival. Moreover, the prognostic role of NDRG4 was stratified by p-AKT. Overexpression of NDRG4 in colorectal cancer cell can significantly suppress PI3K-AKT activity, even after EGF stimulation. These results indicated NDRG4 protein expression was decreased in colorectal cancer. It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity. Therefore, high risk colorectal cancer patients could be better identified based on the combination of NDRG4 and PI3K-AKT activity.

No MeSH data available.


Related in: MedlinePlus

NDRG4 overexpression in SW620 cells reduced PI3K-AKT activation(A) Transfection of pCMV6-NDRG4 significantly increased NDRG4 expression. (B) Overexpression of NDRG4 decreased p-AKT expression. (C) EGF increased p-AKT expression. (D) NDRG4 overexpression suppressed p-AKT even after EGF stimulation.
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Figure 4: NDRG4 overexpression in SW620 cells reduced PI3K-AKT activation(A) Transfection of pCMV6-NDRG4 significantly increased NDRG4 expression. (B) Overexpression of NDRG4 decreased p-AKT expression. (C) EGF increased p-AKT expression. (D) NDRG4 overexpression suppressed p-AKT even after EGF stimulation.

Mentions: As it was proved in clinical specimens that NDRG4 staining negatively correlated with p-AKT, which could stratify the prognostic role of NDRG4, indicating the potential interaction between NDRG4 and p-AKT. Considering the phosphorylation n of AKT is the key regulatory step of PI3K-AKT activation. We speculated that NDRG4 might play its tumor suppressive role through suppression of PI3K-AKT. To confirm this inhibitory effect of NDRG4 on PI3K-AKT activity, we firstly examined whether transfection of pCMV6-NDRG4 could increase NDRG4 expression in tumor cells. As shown in Figure 4A, transfection of pCMV6-NDRG4 in SW620 cells significantly increased NDRG4 expression compared with control cells. Then, we examined the effect of NDRG4 overexpression on p-AKT. Results showed that overexpression of NDRG4 considerably decreased p-AKT expression compared with control cells (Figure 4B). We next investigated the effect of NDRG4 overexpression on p-AKT in response to Epidermal Growth Factor (EGF) stimulation. It was found that the treatment with 5 nM PMA could lead to significant increase of p-AKT expression (Figure 4C). Whereas NDRG4 overexpression strongly suppressed p-AKT even after PMA stimulation (Figure 4D). These results indicated that NDRG4 could effectively suppress PI3K-AKT activity in colorectal cancer.


NDRG4, a novel candidate tumor suppressor, is a predictor of overall survival of colorectal cancer patients.

Chu D, Zhang Z, Zhou Y, Li Y, Zhu S, Zhang J, Zhao Q, Ji G, Wang W, Zheng J - Oncotarget (2015)

NDRG4 overexpression in SW620 cells reduced PI3K-AKT activation(A) Transfection of pCMV6-NDRG4 significantly increased NDRG4 expression. (B) Overexpression of NDRG4 decreased p-AKT expression. (C) EGF increased p-AKT expression. (D) NDRG4 overexpression suppressed p-AKT even after EGF stimulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480701&req=5

Figure 4: NDRG4 overexpression in SW620 cells reduced PI3K-AKT activation(A) Transfection of pCMV6-NDRG4 significantly increased NDRG4 expression. (B) Overexpression of NDRG4 decreased p-AKT expression. (C) EGF increased p-AKT expression. (D) NDRG4 overexpression suppressed p-AKT even after EGF stimulation.
Mentions: As it was proved in clinical specimens that NDRG4 staining negatively correlated with p-AKT, which could stratify the prognostic role of NDRG4, indicating the potential interaction between NDRG4 and p-AKT. Considering the phosphorylation n of AKT is the key regulatory step of PI3K-AKT activation. We speculated that NDRG4 might play its tumor suppressive role through suppression of PI3K-AKT. To confirm this inhibitory effect of NDRG4 on PI3K-AKT activity, we firstly examined whether transfection of pCMV6-NDRG4 could increase NDRG4 expression in tumor cells. As shown in Figure 4A, transfection of pCMV6-NDRG4 in SW620 cells significantly increased NDRG4 expression compared with control cells. Then, we examined the effect of NDRG4 overexpression on p-AKT. Results showed that overexpression of NDRG4 considerably decreased p-AKT expression compared with control cells (Figure 4B). We next investigated the effect of NDRG4 overexpression on p-AKT in response to Epidermal Growth Factor (EGF) stimulation. It was found that the treatment with 5 nM PMA could lead to significant increase of p-AKT expression (Figure 4C). Whereas NDRG4 overexpression strongly suppressed p-AKT even after PMA stimulation (Figure 4D). These results indicated that NDRG4 could effectively suppress PI3K-AKT activity in colorectal cancer.

Bottom Line: Significant negative correlations were found between NDRG4 staining and p-AKT.In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival.It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

ABSTRACT
The role of NDRG4 in human malignancies is largely unknown. We investigated the role of NDRG4 protein in colorectal cancer and its prognostic value in a hospital-based retrospective training cohort of 272 patients and a prospective validation cohort of 708 patients were. Cell line was transfected with an NDRG4 expression construct to confirm the suppression of PI3K-AKT activity by NDRG4. Appropriate statistical methods were utilized for analysis. Results showed that NDRG4 protein expression was significantly decreased from normal mucosa, chronic colitis, ulcerative colitis, atypical hyperplasia to colorectal cancer. Significant negative correlations were found between NDRG4 staining and p-AKT. Patients with positive NDRG4 staining had favorable survival in both study cohorts. In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival. Moreover, the prognostic role of NDRG4 was stratified by p-AKT. Overexpression of NDRG4 in colorectal cancer cell can significantly suppress PI3K-AKT activity, even after EGF stimulation. These results indicated NDRG4 protein expression was decreased in colorectal cancer. It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity. Therefore, high risk colorectal cancer patients could be better identified based on the combination of NDRG4 and PI3K-AKT activity.

No MeSH data available.


Related in: MedlinePlus