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

// Dake Chu 1, 2, * , Zixi Zhang 3, * , Yi Zhou 4, * , Yunming Li 5 , Shaojun Zhu 6 , Jian Zhang 2 , Qingchuan Zhao 1 , Gang Ji 1 , Weizhong Wang 1 , Jianyong Zheng 1 1 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China 2 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China 3 Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China 4 Department of Gastrointestinal Surgery, Tianjin Union Medical Center, Tianjin, China 5 Statistics Office, Chengdu Military General Hospital, Chengdu, Sichuan Province, China 6 Department of Pathology, Fourth Military Medical University, Xi'an, China * These authors have contributed equally to this work Correspondence to: Jianyong Zheng, e-mail: zhjy68@163.com Dake Chu, e-mail: chudake@hotmail.com Keywords: NDRG4, PI3K-AKT, colorectal cancer, carcinogenesis, progression Received: December 16, 2014      Accepted: January 19, 2015      Published: February 05, 2015 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.