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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

IHC staining of NDRG4 and p-AKT(A–E) NDRG4 staining, A normal epithelium, B chronic colonitis, C ulcerative colitis, D dysplasia, E cancer; (F–J) p-AKT staining, F normal epithelium, G chronic colonitis, H ulcerative colitis, I dysplasia, J cancer.
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Figure 1: IHC staining of NDRG4 and p-AKT(A–E) NDRG4 staining, A normal epithelium, B chronic colonitis, C ulcerative colitis, D dysplasia, E cancer; (F–J) p-AKT staining, F normal epithelium, G chronic colonitis, H ulcerative colitis, I dysplasia, J cancer.

Mentions: To understand the role of NDRG4 in colorectal cancer and to determine the potential functional mechanism, we began by investigating NDRG4 expression in clinical specimens and its association with clinicopathological characteristics as well as p-AKT. IHC assay results revealed that NDRG4 staining was mainly located in cytoplasma. Representative staining pattern of NDRG4 and p-AKT was showed in Figure 1. The positive ratio was significantly decreased from normal mucosa (89.7%, Figure 1A), chronic colitis (75.8%, Figure 1B), ulcerative colitis (71.8%, Figure 1C), atypical hyperplasia (58.8%, Figure 1D) to tumor (40.7%, Figure 1E) indicating its tumor suppressive role during the transition from normal mucosa to cancer (P < 0.001). Whereas p-AKT protein expression pattern was opposite to NDRG4 with IHC figures showed in Figure 1F–1J. With respect to the association of NDRG4 with p-AKT staining, there was a significant negative correlation between NDRG4 and p-AKT staining both in the retrospective (r = −0.409, P < 0.001) and prospective study cohorts (r = −0.140, P = 0.018), indicating the potential interaction of the two proteins. To detect the role of NDRG4 in colorectal cancer, we next examined the association of NDRG4 with clinicopathological characteristics in both study cohorts. Statistical analysis results (Table 1) showed that NDRG4 positive staining was significantly associated with tumor well differentiation (P = 0.001), little invasiveness (P = 0.007), absent node metastasis (P = 0.004), absent distant metastasis (P = 0.001) and low TNM stage (P = 0.001), indicating NDRG4 might play tumor suppressive role in colorectal cancer by regulating tumor differentiation, invasion and metastasis. Moreover, NDRG4 positive staining was also more likely to be detected in tumors with wild-type of PI3KCA (P < 0.001).


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)

IHC staining of NDRG4 and p-AKT(A–E) NDRG4 staining, A normal epithelium, B chronic colonitis, C ulcerative colitis, D dysplasia, E cancer; (F–J) p-AKT staining, F normal epithelium, G chronic colonitis, H ulcerative colitis, I dysplasia, J cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: IHC staining of NDRG4 and p-AKT(A–E) NDRG4 staining, A normal epithelium, B chronic colonitis, C ulcerative colitis, D dysplasia, E cancer; (F–J) p-AKT staining, F normal epithelium, G chronic colonitis, H ulcerative colitis, I dysplasia, J cancer.
Mentions: To understand the role of NDRG4 in colorectal cancer and to determine the potential functional mechanism, we began by investigating NDRG4 expression in clinical specimens and its association with clinicopathological characteristics as well as p-AKT. IHC assay results revealed that NDRG4 staining was mainly located in cytoplasma. Representative staining pattern of NDRG4 and p-AKT was showed in Figure 1. The positive ratio was significantly decreased from normal mucosa (89.7%, Figure 1A), chronic colitis (75.8%, Figure 1B), ulcerative colitis (71.8%, Figure 1C), atypical hyperplasia (58.8%, Figure 1D) to tumor (40.7%, Figure 1E) indicating its tumor suppressive role during the transition from normal mucosa to cancer (P < 0.001). Whereas p-AKT protein expression pattern was opposite to NDRG4 with IHC figures showed in Figure 1F–1J. With respect to the association of NDRG4 with p-AKT staining, there was a significant negative correlation between NDRG4 and p-AKT staining both in the retrospective (r = −0.409, P < 0.001) and prospective study cohorts (r = −0.140, P = 0.018), indicating the potential interaction of the two proteins. To detect the role of NDRG4 in colorectal cancer, we next examined the association of NDRG4 with clinicopathological characteristics in both study cohorts. Statistical analysis results (Table 1) showed that NDRG4 positive staining was significantly associated with tumor well differentiation (P = 0.001), little invasiveness (P = 0.007), absent node metastasis (P = 0.004), absent distant metastasis (P = 0.001) and low TNM stage (P = 0.001), indicating NDRG4 might play tumor suppressive role in colorectal cancer by regulating tumor differentiation, invasion and metastasis. Moreover, NDRG4 positive staining was also more likely to be detected in tumors with wild-type of PI3KCA (P < 0.001).

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