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

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.

Differentially regulated ADAMTS1, 8, and 18 in gastric adenocarcinoma

“…The authors also demonstrated that this metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, and inhibits tumor cell motility (20). The other study, reported by Chen et al, showed that ADAMTS8 hypermethylation is associated with decreased expression in GC and may play an important role in the invasion and metastasis of GC (21). According to the fi ndings obtained from our study, positive immunostaining of ADAMTS8 in gastric cancerous tissue and lymph node was higher than in adjacent normal gastric and lymphatic tissues.…”

“…Porter at al also found in their study that high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 were associated with poor prognosis in breast cancer (17). To the best of our knowledge, there are only two clinical studies on the potential role of ADAMTS8 in GC (20,21). Both studies focused on the angioinhibitory effects of ADAMTS8, and mainly examined the methylation status of this protease.…”

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer

“…Of note, most of the top-ranking sLungGenes identified in our study are not exclusively expressed in the adult lung (Supplemental Figures 1-3), and these genes also have reported roles in other types of cancer (Supplemental Table 2). For example, ADAMTS8, which encodes a secreted protease with antiangiogenic properties, is a tumor suppressor that is silenced not only in lung carcinoma (79) but also in many other cancers, including brain tumors (80), breast carcinoma (81), head and neck squamous cell carcinoma (82), pancreatic cancer (83), and gastric or colorectal cancers (84). Likewise, WIF1 has been described as a tumor suppressor in lung cancer (85)(86)(87)(88) and in osteosarcoma (89), kidney cancer (90), and pleomorphic adenoma (91).…”

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

“…Similar results to those observed for ADAMTS5 were reported for other members of the family, such as ADAMTS8 and ADAMTS9. In GC, the methylation status of ADAMTS8 inversely correlates with the protein expression and lower ADAMTS8 levels associate with a higher invasive depth and with the presence of lymph node metastasis [271]. The promoters of ADAMTS8 and ADAMTS9 are methylated also in CRC and this correlates with a decreased expression of these proteases [272][273][274].…”

“…Despite the documented activity of these proteases in the regulation of angiogenesis, in the context of GI tumors it is widely accepted. Only in some studies has an inverse correlation between ADAMTS expression and tumor microvessel density or VEGFA expression been clearly described [267,270,271]. However, the precise molecular mechanism behind the role of ADAMTS proteins in vasculogenesis is still under investigation.…”