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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

Kaplan-Meier survival curves of patients in the retrospective study cohort(A) Correlation of NDRG4 staining with overall survival. (B) Correlation of p-AKT staining with overall survival among patients with tumors with positive NDRG4 staining. (C) Correlation of p-AKT staining with overall survival among patients with tumors with negative NDRG4 staining. (D) Survival curves for patients with aberrant NDRG4 and p-AKT coexpression.
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Figure 2: Kaplan-Meier survival curves of patients in the retrospective study cohort(A) Correlation of NDRG4 staining with overall survival. (B) Correlation of p-AKT staining with overall survival among patients with tumors with positive NDRG4 staining. (C) Correlation of p-AKT staining with overall survival among patients with tumors with negative NDRG4 staining. (D) Survival curves for patients with aberrant NDRG4 and p-AKT coexpression.

Mentions: Given the strong association between NDRG4 and colorectal cancer differentiation, invasion and metastasis, we further investigate its prognostic role utilized the cut-off point of positive and negative staining of NDRG4. In the retrospective data set including 272 patients, 148 (54.4%) patients were dead at the end of follow-up. Survival analysis by Kaplan-Meier estimate and log-rank test revealed that the presence of NDRG4 positive staining was significantly associated with favorable outcome (log-rank test: P < 0.001; Figure 2A). The median survival time of patients with negative (−) staining of NDRG4 was 52 months (95% CI: 47.3–56.7), while that of patients with positive (+) staining of NDRG4 cannot be estimated due to better survival. Patients with negative NDRG4 staining tended to have a higher risk of death, with an unadjusted hazard ratio (HR) of 2.18 (95% CI: 1.11–4.33; P < 0.001). In addition, differentiation status, lymph node metastasis, TNM stage, KRAS, BRAF, PIK3CA mutations and MSI were also found to be associated with prognosis. However, sex, age, tumor location, tumor size or vascular invasion had no prognostic value (Table 2). Starting from these covariates, we constructed a multivariate prognostic model that considered the significant risk factors by using a stepwise selection procedure. Multivariate Cox regression adjusted for sex, age, differentiation status, TNM stage, KRAS, BRAF and PIK3CA mutations and MSI showed that negative NDRG4 staining was significantly and independently associated with poor overall survival, with an adjusted HR of 2.35 (95% CI: 1.15–4.61; P < 0.001). Thus, NDRG4 staining constitutes a powerful prognostic biomarker independent of adjusted clinical variables in retrospective cohort (Table 2).


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)

Kaplan-Meier survival curves of patients in the retrospective study cohort(A) Correlation of NDRG4 staining with overall survival. (B) Correlation of p-AKT staining with overall survival among patients with tumors with positive NDRG4 staining. (C) Correlation of p-AKT staining with overall survival among patients with tumors with negative NDRG4 staining. (D) Survival curves for patients with aberrant NDRG4 and p-AKT coexpression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Kaplan-Meier survival curves of patients in the retrospective study cohort(A) Correlation of NDRG4 staining with overall survival. (B) Correlation of p-AKT staining with overall survival among patients with tumors with positive NDRG4 staining. (C) Correlation of p-AKT staining with overall survival among patients with tumors with negative NDRG4 staining. (D) Survival curves for patients with aberrant NDRG4 and p-AKT coexpression.
Mentions: Given the strong association between NDRG4 and colorectal cancer differentiation, invasion and metastasis, we further investigate its prognostic role utilized the cut-off point of positive and negative staining of NDRG4. In the retrospective data set including 272 patients, 148 (54.4%) patients were dead at the end of follow-up. Survival analysis by Kaplan-Meier estimate and log-rank test revealed that the presence of NDRG4 positive staining was significantly associated with favorable outcome (log-rank test: P < 0.001; Figure 2A). The median survival time of patients with negative (−) staining of NDRG4 was 52 months (95% CI: 47.3–56.7), while that of patients with positive (+) staining of NDRG4 cannot be estimated due to better survival. Patients with negative NDRG4 staining tended to have a higher risk of death, with an unadjusted hazard ratio (HR) of 2.18 (95% CI: 1.11–4.33; P < 0.001). In addition, differentiation status, lymph node metastasis, TNM stage, KRAS, BRAF, PIK3CA mutations and MSI were also found to be associated with prognosis. However, sex, age, tumor location, tumor size or vascular invasion had no prognostic value (Table 2). Starting from these covariates, we constructed a multivariate prognostic model that considered the significant risk factors by using a stepwise selection procedure. Multivariate Cox regression adjusted for sex, age, differentiation status, TNM stage, KRAS, BRAF and PIK3CA mutations and MSI showed that negative NDRG4 staining was significantly and independently associated with poor overall survival, with an adjusted HR of 2.35 (95% CI: 1.15–4.61; P < 0.001). Thus, NDRG4 staining constitutes a powerful prognostic biomarker independent of adjusted clinical variables in retrospective cohort (Table 2).

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