The metastasis suppressor, NDRG1, inhibits “stemness” of colorectal cancer via down-regulation of nuclear β-catenin and CD44
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Xiongzhi Wangpu1,2,3, Xiao Yang1,2,4, Jingkun Zhao1,2, Jiaoyang Lu1,2, Shaopei Guan1,4, Jun Lu1,2, Zaklina Kovacevic3, Wensheng Liu1, Lan Mi1, Runsen Jin1, Jing Sun1,2, Fei Yue1,2, Junjun Ma1,2, Aiguo Lu1,2,4, Des R. Richardson3, Lishun Wang5, Minhua Zheng1,2,4
1Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
2Shanghai Minimally Invasive Surgery Center, Shanghai, 200025, China
3Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia
4Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
5The Division of Translational Medicine, Minhang Hospital, Fudan University, Shanghai, 201199, China
Minhua Zheng, e-mail: [email protected]
Lishun Wang, e-mail: [email protected]
Des R. Richardson, e-mail: [email protected]
Keywords: β-catenin, colorectal cancer, NDRG1, stem cell-like property, tumorigenesis
Received: March 18, 2015 Accepted: September 04, 2015 Published: September 18, 2015
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.
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