Silencing NKD2 by promoter region hypermethylation promotes gastric cancer invasion and metastasis by up-regulating SOX18 in human gastric cancer

Naked cuticle homolog2 (NKD2) is located in chromosome 5p15.3, which is frequently loss of heterozygosity in human colorectal and gastric cancers. In order to understand the mechanism of NKD2 in gastric cancer development, 6 gastric cancer cell lines and 196 cases of human primary gastric cancer samples were involved. Methylation specific PCR (MSP), gene expression array, flow cytometry, transwell assay and xenograft mice model were employed in this study. The expression of NKD1 and NKD2 was silenced by promoter region hypermethylation. NKD1 and NKD2 were methylated in 11.7% (23/196) and 53.1% (104/196) in human primary gastric cancer samples. NKD2 methylation is associated with cell differentiation, TNM stage and distant metastasis significantly (all P < 0.05), and the overall survival time is longer in NKD2 unmethylated group compared to NKD2 methylated group (P < 0.05). Restoration of NKD2 expression suppressed cell proliferation, colony formation, cell invasion and migration, induced G2/M phase arrest, and sensitized cancer cells to docetaxel. NKD2 inhibits SOX18 and MMP-2,7,9 expression and suppresses BGC823 cell xenograft growth. In conclusion, NKD2 methylation may serve as a poor prognostic and chemo-sensitive marker in human gastric cancer. NKD2 impedes gastric cancer metastasis by inhibiting SOX18.National Basic Research Program of China (973 Program) [2012CB934002, 2015CB553904]; National High-tech R&D Program of China (863 Program) [SS2012AA020314, SS2012AA020821, SS2012AA020303]; National Key Scientific Instrument Special Programme of China [2011YQ03013405]; National Science Foundation of China (NSFC) [81402345, 81121004, 81161120432, 81490753, 81401950]; Tianjin Research Program of Application Foundation & Advanced Technology [14JCQNJC12400]; Science and Technology Development Program of Tianjin High School [20120115]SCI(E)PubMedARTICLEHermanj3@upmc.edu; mzguo@hotmail.com3233470-33485