ADAM17 promotes lymph node metastasis in gastric cancer via activation of the Notch and Wnt signaling pathways

Abstract

Disintegrin and metalloproteinase domain-containing proteins (ADAMs) have been implicated in cell adhesion, signaling and migration. The aim of the present study was to identify key members of the ADAM protein family associated with the metastasis of gastric cancer and to evaluate their clinical significance. A total of 193 patients with gastric cancer and positive lymph node metastasis were enrolled. Key members of the ADAM family associated with lymph node metastasis were identified. The correlations between survival times and the clinicopathological features of patients were investigated. Furthermore, ADAM17 expression in gastric cancer cells with different metastatic potentials was determined. ADAM17 was overexpressed in BGC-823 cells and suppressed in SGC-7901 cells to further investigate its effects on cell viability and migration. The key pathways associated with ADAM17 were identified by gene set enrichment analysis (GSEA). It was found that ADAM9 and ADAM17 were significantly upregulated in gastric cancer and positive metastatic lymph node tissues. Further, there was a strong correlation between the survival times of patients and ADAM17 expression. ADAM17 was upregulated in gastric cancer cells with high metastatic potential. The viability of BGC-823 cells significantly increased following ADAM17 overexpression, whereas the viability and migration of SGC-7901 cells decreased following ADAM17 suppression. GSEA and western blot analysis revealed a positive correlation between the Notch and Wnt signaling pathways with ADAM17 expression. In conclusion, the increased expression of ADAM17 promoted the progression of gastric cancer, potentially via Notch and/or Wnt signaling pathway activation, and ADAM17 may serve as a useful prognostic marker.

Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells

“…ADAM17 encodes ADAM metallopeptidase domain 17, a member of a disintegrin and metalloprotease domain family, and is also known as tumor necrosis factor (TNF)-converting enzyme (Li et al, 2019c). A previous study demonstrated that ADAM17 plays a role in the shedding of TNFα and membrane receptors protein, which involved in the biological process of proliferation, migration, and differentiation (Gutiérrez-López et al, 2011).…”

“…pathway (Li et al, 2018), and induces metastasis in gastric cancer through activation of Notch and Wnt signaling pathways (Li et al, 2019c). A review article discussed ADAM17 inhibitors for inflammation and cancer therapy (Kanda et al, 2017).…”

MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

“…It has been confirmed that Notch protein is cleaved and activated by the ADAM metalloprotease domain-17 . This results in the release of the Notch intracellular domain (NICD) for translocation into the nucleus to mediate the transcription of pro-survival or anti-apoptosis genes, such as Survivin, B-cell lymphoma-2, or inhibitors of apoptosis proteins (IAPs) [26][27][28] . Increasing evidence demonstrated that inhibition of the activation of the Notch pathway may enhance the efficiency of antitumor agents in HCC cells 29,30 .…”

Identification of F5 as a Prognostic Biomarker in Patients with Gastric Cancer

“…BioMed Research International of gastric cancer [29]. Li et al also showed that the activation of the Notch signalling pathway regulates the development and progression of gastric cancer [30]. Tight junctions (TJ) located between cells play important roles in paracellular sol-ute transport and cell polarity maintenance.…”