Abstract
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.
Highlights
Almost one million new cases of stomach cancer were estimated to have occurred in 2012, making it the fifth most common malignancy in the world
Naked cuticle homolog1 (NKD1) and Naked cuticle homolog2 (NKD2) expression are silenced by promoter region hypermethylation in gastric cancer cell lines
No NKD2 expression changes were demonstrated in the unmethylated SGC7901 and MKN45 cells. These results suggest that the expression levels of NKD1 and NKD2 are regulated by promoter region methylation in human gastric cancer cells
Summary
Almost one million new cases of stomach cancer were estimated to have occurred in 2012, making it the fifth most common malignancy in the world. In roughly 30% of familial gastric cancers, a germline mutation in one allele of the E-cadherin gene (CDH1) can be identified. The estimated life-time risk of developing gastric cancer in carriers of a CDH1 mutation is 67% in men and 83% in women [5,6,7]. According to a recent study that performed targeted deep sequencing in 167 cases of gastric cancer, TP53 was among the most commonly mutated genes (35%). A number of tumor suppressor genes, such as hMLM1, p14, p15, p16, GSTP1, RASSF1, COX-2, APC, CDH1, CDH4, DAP-K, THBS1, TIMP-3, RARβ, MGMT, CHFR, DCC, RUNX3, TSLC1, BCL2L10, IRX1, CMDM and UCHL1, are frequently silenced by hypermethylation in gastric cancer [9,10,11,12]
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