The metastasis suppressor, NDRG1, inhibits “stemness” of colorectal cancer via down-regulation of nuclear β-catenin and CD44

// Xiongzhi Wangpu 1, 2, 3 , Xiao Yang 1, 2, 4 , Jingkun Zhao 1, 2 , Jiaoyang Lu 1, 2 , Shaopei Guan 1, 4 , Jun Lu 1, 2 , Zaklina Kovacevic 3 , Wensheng Liu 1 , Lan Mi 1 , Runsen Jin 1 , Jing Sun 1, 2 , Fei Yue 1, 2 , Junjun Ma 1, 2 , Aiguo Lu 1, 2, 4 , Des R. Richardson 3 , Lishun Wang 5 , Minhua Zheng 1, 2, 4 1 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 2 Shanghai Minimally Invasive Surgery Center, Shanghai, 200025, China 3 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia 4 Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 5 The Division of Translational Medicine, Minhang Hospital, Fudan University, Shanghai, 201199, China Correspondence to: Minhua Zheng, e-mail: wangpuxz@hotmail.com Lishun Wang, e-mail: lishunwang@fudan.edu.cn Des R. Richardson, e-mail: d.richardson@med.usyd.edu.au Keywords: β-catenin, colorectal cancer, NDRG1, stem cell-like property, tumorigenesis Received: March 18, 2015 Accepted: September 04, 2015 Published: September 18, 2015 ABSTRACT N-myc downstream-regulated gene 1 (NDRG1), has been identified as an important metastasis suppressor for colorectal cancer (CRC). In this study, we investigated: (1) the effects of NDRG1 on CRC stemness and tumorigenesis; (2) the molecular mechanisms involved; and (3) the relationship between NDRG1 expression and colorectal cancer prognosis. Our investigation demonstrated that CRC cells with silenced NDRG1 showed more tumorigenic ability and stem cell-like properties, such as: colony and sphere formation, chemoresistance, cell invasion, high expression of CD44, and tumorigenicity in vivo . Moreover, NDRG1 silencing reduced β-catenin expression on the cell membrane, while increasing its nuclear expression. The anti-tumor activity of NDRG1 was demonstrated to be mediated by preventing β-catenin nuclear translocation, as silencing of this latter molecule could reverse the effects of silencing NDRG1 expression. NDRG1 expression was also demonstrated to be negatively correlated to CRC prognosis. In addition, there was a negative correlation between NDRG1 and nuclear β-catenin and also NDRG1 and CD44 expression in clinical CRC specimens. Taken together, our investigation demonstrates that the anti-metastatic activity of NDRG1 in CRC occurs through the down-regulation of nuclear β-catenin and suggests that NDRG1 is a significant therapeutic target.