Journal
ONCOTARGET
Volume 6, Issue 32, Pages 33893-33911Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5294
Keywords
beta-catenin; colorectal cancer; NDRG1; stem cell-like property; tumorigenesis
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Funding
- National High Technology Research and Development Program 863 [2012AA021103]
- Basic Research Project of Shanghai Municipal Science and Technology Commission [13JC1404100]
- Shanghai Science & Technology Committee [14YF1402800]
- National Natural Science Foundation [81201625, 81402423, 31170783, 81472758, U1302225]
- National Health and Medical Research Council (NHMRC)
- NHMRC
- Cancer Institute New South Wales Early Career Fellowship
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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 beta-catenin expression on the cell membrane, while increasing its nuclear expression. The antitumor activity of NDRG1 was demonstrated to be mediated by preventing beta-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 beta-catenin and also NDRG1 and CD44 expression in clinical CRC specimens. Taken together, our investigation demonstrates that the antimetastatic activity of NDRG1 in CRC occurs through the down-regulation of nuclear beta-catenin and suggests that NDRG1 is a significant therapeutic target.
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