Premium
Epigenetic silencing of NDRG2 promotes colorectal cancer proliferation and invasion
Author(s) -
Hong Sung Noh,
Kim Sung Jin,
Kim EunRan,
Chang Dong Kyung,
Kim YoungHo
Publication year - 2016
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.13068
Subject(s) - gene silencing , medicine , epigenetics , colorectal cancer , cancer research , cancer , genetics , gene , biology
Abstract Background: Genome‐wide methylation arrays have revealed aberrant methylation of N‐Myc downstream‐regulated gene 2 ( NDRG2 ) promoter in colorectal cancer (CRC). This study investigated the role of NDRG2 in colorectal carcinogenesis. Methods: The aberrant promoter methylation, mRNA, and protein expression of NDRG2 were evaluated in 27 pairs of human CRC and adjacent normal tissues and seven human CRC‐derived cell‐lines. After stable NDRG2 over‐expressed RKO and DLD‐1 human CRC cell‐lines were constructed, in vitro functional assays, including colony formation, cell viability, proliferation, invasion and migration assays, and in vivo xenograft models were performed. Results: The promoter of NDRG2 was methylated in 89% human CRC tissue compared to adjacent normal colonic mucosa (7.4%; P < 0.001). High‐level methylation of NDRG2 promoter was more prevalent in proximal CRC ( P = 0.022) and advanced T stage ( P = 0.039). NDRG2 mRNA and protein expression was down‐regulated in 89% and 100% human CRC tissue, respectively. In human CRC cell‐lines, the promoter of NDRG2 was methylated aberrantly and mRNA, and protein expression of NDRG2 was down‐regulated. NDRG2 mRNA expression was reactivated by 5‐aza‐2′‐deoxycytidine. Colony formation of NDRG2 over‐expressing RKO cells was inhibited ( P = 0.012), as was the viability, proliferation, and invasion of NDRG2 over‐expressing DLD‐1 cells ( P < 0.001, P = 0.003, and P = 0.044, respectively). Tumor volume in xenograft mice transplanted with NDRG2 over‐expressing RKO and DLD‐1 cells was smaller than that in controls ( P = 0.002 and P = 0.001, respectively). Conclusions: Epigenetic silencing of NDRG2 induces proliferation and invasion of CRC and may be associated with proximal CRC and advanced T stage. NDRG2 methylation might serve as novel biomarker of CRC.