Downregulation of ADAMTS8 by DNA Hypermethylation in Gastric Cancer and Its Clinical Significance.

Jing Chen,Chundong Zhang,Hongbin Zhang,Xin Li,Jiakui Zhang,Junzhe Jin,Dongqiu Dai

doi:10.1155/2016/5083841

Abstract

A disintegrin and metallopeptidase with thrombospondin motif type 8 (ADAMTS8), a member of the ADAMTS family, was discovered as a novel angiogenesis inhibitor. We analyzed the expression and methylation of ADAMTS8 in primary gastric tumors and gastric cancer cell lines. We also examined the relationship between ADAMTS8 expression and methylation and clinicopathologic features. The results showed that the significant downregulation of ADAMTS8 mRNA expression was observed in gastric cancer cell lines and tissues, and its expression was related to invasive depth and lymph node metastasis. CpG was hypermethylated in gastric cancer cell lines MKN45, MGC803, and BGC823, as well as primary gastric cancer specimens. ADAMTS8 mRNA expression was significantly lower in methylated primary gastric tumors. A significant association was found between ADAMTS8 methylation status and lymph node metastasis in primary gastric cancer. Moreover, ADAMTS8 expression was upregulated in the gastric cancer cell lines MGC803, BGC823, and MKN45 after treatment with 5-aza-2′-deoxycytidine. Thus, our results demonstrate that expression of ADAMTS8 mRNA is significantly decreased and DNA methylation is frequent in gastric cancer. ADAMTS8 hypermethylation is associated with decreased expression in gastric cancer and may play an important role in the invasion and metastasis of gastric cancer.

Highlights

Gastric cancer is one of the most common digestive malignancies worldwide, and more than 70% of new cases and deaths occur in developing countries [1]
The results showed that ADAMTS8 mRNA expression was significantly lower in the gastric cancer cell lines SGC7901 (0.85-fold), MGC803 (0.43-fold), BGC823 (0.19-fold), and MKN45 (0.13fold) compared to the normal gastric cell line GES1 (1-fold as the control) (Figure 1(a))
We found that ADAMTS8 was downregulated in gastric cancer cell lines compared to normal gastric cells

Summary

Introduction

Gastric cancer is one of the most common digestive malignancies worldwide, and more than 70% of new cases and deaths occur in developing countries [1]. Many studies have demonstrated that epigenetic alterations, including DNA methylation and histone modifications, may result in the silencing of cancer-related genes. A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs), a family of extracellular matrix metalloproteinase that contains 19 members, are similar to matrix metalloproteinases (MMPs) and ADAMs in structure and function [6]. ADAMTSs are secreted extracellular enzymes that have a compound domain organization comprising a signal peptide followed by a proregion of variable length, a metalloproteinase domain, a disintegrin-like domain, a central thrombospondin type 1 sequence repeat motif, and a cysteine-rich domain followed by a spacer region [7]. Recent studies have provided evidence of dysregulated ADAMTS expression in diverse types of cancers including gastric, colorectal, pancreatic, lung, esophageal, nasopharyngeal, and breast cancers [17,18,19,20,21]. ADAMTS8, known as METH-2, is a member of the ADAMTS family and is originally identified as one of the antiangiogenic

Methods

Results

Conclusion