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Abstract
Helicobacter pylori (H. pylori) infection promotes the metastasis of gastric carcinoma cells by modulating signal transduction pathways that regulate cell proliferation, motility, and invasion. Astaxanthin (ASTX), a xanthophyll carotenoid, is known to inhibit cancer cell migration and invasion, however the mechanism of action of ASTX in H. pylori-infected gastric epithelial cells is not well understood. To gain insight into this process, we carried out a comparative RNA sequencing (RNA-Seq) analysis of human gastric cancer AGS (adenocarcinoma gastric) cells as a function of H. pylori infection and ASTX administration. The results were used to identify genes that are differently expressed in response to H. pylori and ASTX. Gene ontology (GO) analysis identified differentially expressed genes (DEGs) to be associated with cell cytoskeleton remodeling, motility, and/or migration. Among the 20 genes identified, those encoding c-MET, PI3KC2, PLCγ1, Cdc42, and ROCK1 were selected for verification by real-time PCR analysis. The verified genes were mapped, using signaling networks contained in the KEGG database, to create a signaling pathway through which ASTX might mitigate the effects of H. pylori-infection. We propose that H. pylori-induced upregulation of the upstream regulator c-MET, and hence, its downstream targets Cdc42 and ROCK1, is suppressed by ASTX. ASTX is also suggested to counteract H. pylori-induced activation of PI3K and PLCγ. In conclusion, ASTX can suppress H. pylori-induced gastric cancer progression by inhibiting cytoskeleton reorganization and reducing cell motility through downregulation of c-MET, EGFR, PI3KC2, PLCγ1, Cdc42, and ROCK1.
Highlights
Gastric cancer is the fifth most common type of cancer and the third leading cause of death from cancer [1]
We focused our attention on five of these, namely the c-MET, PI3KC2β, PLCγ1, cell division control protein 42 (Cdc42), and ROCK1 encoding genes, and demonstrated that their transcription is upregulated by H. pylori, but significantly less so in ASTX-pretreated AGS
We found that ASTX treatment significantly reduces upregulated c-MET gene expression in H. pylori-infected AGS cells (Table 1, Figure 3)
Summary
Gastric cancer is the fifth most common type of cancer and the third leading cause of death from cancer [1]. Helicobacter pylori infection is the major cause of gastric cancer, accounting for more than 60% of the cases [2]. Gastric cancer metastasizes at a high rate, localizing primarily in the liver, peritoneum, lung, and bone [3]. Metastatic cancer occurs as a result of the invasion of the surrounding stroma by primary tumor cells, followed by intravasation of the primary tumor into lymphatic or blood vessels, and by extravasation and colonization of the tumor cells at a distant organ site [4]. Metastasis is initiated when cancer cells acquire specialized behaviors that allow them to breach the basement membrane of the extracellular matrix (ECM). Modulation of cell motility is the determinant step in early local invasion. Cell motility requires continuous turnover of the cytoskeleton and modification of cell–cell and cell–substratum adhesions [6]
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