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

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.

Low NKD1 expression predicts adverse prognosis in cytogenetically normal acute myeloid leukemia

“…[12][13][14][15][16] Decreased expression of NKD1 probably caused by its promoter hypermethylation has been reported in human cancer including primary hepatocellular carcinoma, small lung adenocarcinoma, breast invasive ductal carcinoma, and gastric cancer. [12][13][14][15][16] However, a few studies also observed increased expression of NKD1 in human hepatoblastomas and colon tumors. 30,31 These results indicated that NKD1 played different roles in different types of human cancers.…”

“…11 Reduced NKD1 expression has been increasingly demonstrated in several solid tumors. [12][13][14][15][16] However, the status of NKD1 expression and its clinical implication in AML remain largely elusive. Therefore, we focused on the NKD1 expression and its clinical significance in de novo patients with AML.…”

Galectin-1 from cancer-associated fibroblasts induces epithelial–mesenchymal transition through β1 integrin-mediated upregulation of Gli1 in gastric cancer

“…A high proportion of deaths related to GC is caused by tumor metastasis, postoperative recurrence, and delayed detection of advanced stage disease [2, 3]. During the process of metastasis and invasion, tumor cells are able to induce a series of changes characterized by diffusible growth factors and cytokines, components of the extracellular matrix, fibroblasts, and myofibroblasts (also called cancer-associated fibroblasts [CAFs]), comprising the tumor microenvironment [4].…”

Role of the SOX18 protein in neoplastic processes (Review)

“…Research by Jia et al (42) was carried out on material from 196 cases of stomach cancer and the 6 human stomach cancer cell lines SGC7901, MGC803, BGC823, AGS, N87 and MKN45. In these experiments, the authors determined the level of methylation of the naked cuticle homolog (NKD) -1 and -2 gene promoters, SOX18 direct inhibitors, on the aforementioned material.…”

“…In these experiments, the authors determined the level of methylation of the naked cuticle homolog (NKD) -1 and -2 gene promoters, SOX18 direct inhibitors, on the aforementioned material. It turned out that the methylation of the NKD1 gene is influenced, among others, by the ability of the cancer cells to migrate and create metastases (42). In turn, the active NKD2 protein effectively inhibits cell proliferation and colony formation, and it also stops the cell cycle at the G2/M control point.…”