Abstract
BackgroundAngiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinically effective in treating GPL. Here, we evaluated WPX’s anti-angiogenic potential for GPL, and also investigated the possibility of its anti-angiogenic mechanisms.MethodsHPLC analysis was applied to screen the major chemical components of WPX. After modeling N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced GPL in male Sprague-Dawley rats, different doses of WPX were administrated orally for 10 weeks. Next, we performed histopathological examination using routine H&E staining and HID-AB-PAS staining. In parallel, we assessed angiogenesis revealed by microvessel density (MVD) using CD34 immunostaining, and subsequently observe microvessel ultrastructure in gastric mucosa under Transmission Electron Microscope. Finally, we detect expression of angiogenesis-associated markers VEGF and HIF-1α using immunohistochemistry. Moreover, mRNA expressions of ERK1, ERK2, Cylin D1 as well as HIF-1α in gastric mucosa were determined by quantitative real-time reverse transcription- polymerase chain reaction.ResultsWe observed the appearance of active angiogenesis in GPL rats, and demonstrated that WPX could reduce microvascular abnormalities and attenuate early angiogenesis in most of GPL specimens with a concomitant regression of most intestinal metaplasia (IM) and a portion of gastric epithelial dysplasia (GED). In parallel, WPX could suppress HIF-1α mRNA expression (P < 0.01) as well as protein expression (although without statistical significance), and could markedly inhibit VEGF protein expression in GPL rats. Mechanistically, WPX intervention, especially at low dose, caused a significant decrease in the ERK1 and Cylin D1 mRNA levels. However, WPX might probably have no regulatory effect on ERK2 amplification.ConclusionsWPX could attenuate early angiogenesis and temper microvascular abnormalities in GPL rats. This might be partly achieved by inhibiting on the angiogenesis-associated markers HIF-1α and VEGF, and on the ERK1/Cylin D1 aberrant activation.
Highlights
Angiogenesis is a pathobiological hallmark of gastric cancer
Hypoxia inducible factor-1α (HIF-1α) has been proved to be a key regulator of cellular adaptation to hypoxia involved in angiogenesis process, and the process is frequently accompanied by a concomitant aberrant activation of vascular endothelial growth factor (VEGF) [14], which is essential for vascular development and can induce proliferation, differentiation and apoptosis of endothelial cells
CD34 antibody was abtained from R&D Systems, USA; VEGF antibody was supplied by Abcam, UK; HIF-1α antibody was purchased from Santa Cruz Biotechnology, USA
Summary
Rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Hypoxia inducible factor-1α (HIF-1α) has been proved to be a key regulator of cellular adaptation to hypoxia involved in angiogenesis process, and the process is frequently accompanied by a concomitant aberrant activation of vascular endothelial growth factor (VEGF) [14], which is essential for vascular development and can induce proliferation, differentiation and apoptosis of endothelial cells. Aberrant activation of ERK signaling is closely linked to the carcinogenesis and development of gastric cancer [16]. Cyclin D1 is frequently overexpressed in a substantial proportion of gastric cancer, and its expression may be governed by the ERK signaling [19, 20]. Studies reported in recent years have addressed the pro-angiogenic role of the molecules in gastric cancer, it is unclear what role the molecules may play in gastric precancerosis
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