Abstract
Helicobacter pylori (H. pylori) infection promotes gastric carcinogenesis by increasing oxidative stress, inflammation, and dysregulation of cell survival and proliferation of gastric epithelial cells. Astaxanthin (ASTX), a bioactive carotenoid, exhibits antioxidant and anticancer effects by modulating aberrant signaling pathways that lead to dysregulation of cell death and proliferation. To elucidate the molecular mechanism of H. pylori-induced gastric carcinogenesis and to examine the inhibitory effect of ASTX on H. pylori-induced gastric epithelial cell gene expression changes, we performed comparative RNA-sequencing (RNA-Seq) analysis for H. pylori-infected gastric epithelial cells treated with or without ASTX. RNA-Seq results reveal that differentially expressed genes (DEGs) in H. pylori-infected cells were mainly associated with the Wnt/β-catenin signaling pathway, which is related to cell proliferation. ASTX significantly reversed H. pylori-induced transcriptional alterations of the key mediators involved in β-catenin signaling, notably, porcupine (gene symbol, PORCN), spermine oxidase (SMOX), bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI), SMAD family member 4 (SMAD4), transforming growth factor-β1 (TGFB1), Fos-like 1 (FOSLI), and c-myc (MYC). We suggest that ASTX may be a potential therapeutic agent that can suppress H. pylori-induced proliferation-associated gene expression changes, in part, by counter-regulating the Wnt/β-catenin signaling pathway.
Highlights
Gastric cancer is the third leading cause of cancer-related mortality worldwide [1].Helicobacter pylori (H. pylori) infection is a major risk factor for the development of gastric cancer [2]
Increased proliferation of gastric epithelial cells is a hallmark feature in gastric carcinogenesis, and the Wnt/β-catenin signaling pathway is the most prominent axis associated with H. pylori-induced hyper-proliferation [5]
We evaluated the regulatory potential of ASTX on the H. pylori-induced oncogenic pathways and identified the key mediators associated with its inhibitory effect
Summary
Gastric cancer is the third leading cause of cancer-related mortality worldwide [1]. Helicobacter pylori (H. pylori) infection is a major risk factor for the development of gastric cancer [2]. Increased proliferation of gastric epithelial cells is a hallmark feature in gastric carcinogenesis, and the Wnt/β-catenin signaling pathway is the most prominent axis associated with H. pylori-induced hyper-proliferation [5]. Aberrant mutations affecting the Wnt/β-catenin signaling pathway often lead to dysregulation of homeostasis and development of cancers. We showed that carotenoids β-carotene and astaxanthin (ASTX) inhibit H. pylori-induced expression of β-catenin target oncogenes c-myc and cyclins (cyclin E or cyclin D1) in gastric epithelial cells in vitro [9] and in gastric mucosal tissues in vivo [10]. Based on its diverse antioxidative properties as well as its direct regulatory function in molecular transcription and activation, ASTX has been demonstrated to be an effective bioactive agent for suppressing cancer cell proliferation and migration [14,15,16]. We propose a signaling network through which ASTX might counteract the effects of H. pylori infection—namely, H. pylori-induced gastric hyper-proliferation
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