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.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth most prevalent cause of tumorrelated death worldwide [1, 2]
Increasing evidence demonstrates that N-myc downstream-regulated gene 1 (NDRG1) functions as a metastasis suppressor and potentially could be a novel indicator for colorectal cancer (CRC) prognosis [16, 25, 52]
NDRG1 has been defined as a metastasis suppressor gene, it is of interest that NDRG1 mRNA expression was found to be up-regulated in colorectal cancer data from the Cancer Genome Atlas (TCGA) [53]
Summary
Colorectal cancer (CRC) is the third most common cancer and the fourth most prevalent cause of tumorrelated death worldwide [1, 2]. The epithelial to mesenchymal transition (EMT) is an embryonic process during which polarized epithelial cells transform into a more motile and mesenchymal phenotype [6] This reversible process generates obvious changes in www.impactjournals.com/oncotarget cell morphology and tumor behavior, such as metastasis and chemoresistance [7, 8]. It is commonly regarded that the gain of a mesenchymal phenotype is associated with some functional traits of cancer stem cell-like cells (CSCs) [9, 10] These CSC properties are considered to be closely correlated with tumor initiation, progression and metastasis, as well as resistance to chemotherapy [11,12,13]. Some studies have demonstrated that the EMT is essential for tumor metastasis, it is not a requirement for the acquisition of CSC properties [14, 15]
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