Abstract
Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. Glutamine: fructose-6-phosphate amidotransferase 1 (GFAT1) is the first and rate-limiting enzyme of hexosamine biosynthesis pathway (HBP). Nevertheless, the role of GFAT1 in gastric cancer is little investigated. In this study, we found that the expression of GFAT1 was decreased in gastric cancer. Low expression of GFAT1 was positively associated with vessel invasion, late T stage, lymph node metastasis, distant metastasis, advanced TNM stage and poor prognosis in patients with gastric cancer. Furthermore, in vitro and in vivo studies revealed that down-regulation of GFAT1 promoted epithelial-to-mesenchymal transition (EMT) and invasive activities in gastric cancer cells through inducing the expression of TGF-β1. The GFAT1 expression also significantly correlated with EMT-related factors in gastric cancer patients. Together, these findings indicate that GFAT1 functions as a novel suppressor of EMT and tumor metastasis in gastric cancer.
Highlights
Gastric cancer remains the fifth most frequent and third leading cause of cancer-related mortality worldwide, though its incidence has decreased over the past six decades [1, 2]
To understand whether Glutamine: fructose-6-phosphate amidotransferase 1 (GFAT1) was involved in gastric carcinogenesis, we first examined the mRNA expression of GFAT1 in paired fresh gastric cancer tissues
Results showed that the mRNA expression of GFAT1 was remarkably decreased in gastric cancer samples from GSE13911 dataset, while no significant difference was observed in the GSE27342 dataset, suggesting the heterogeneity of gastric carcinoma (Figure 1B)
Summary
Gastric cancer remains the fifth most frequent and third leading cause of cancer-related mortality worldwide, though its incidence has decreased over the past six decades [1, 2]. The Asian countries account for the majority of gastric cancer cases, and almost 50% of the world’s cases are diagnosed in China [3, 4]. The high rate of invasion and metastasis represents the major cause for its poor prognosis. It was reported that lymph node metastasis presented in more than 50% of gastric cancer patients when they were initially diagnosed [6], while peritoneum metastasis might be already present in 5% to 20% of patients undergoing gastric resection in curative intent [7]. Epithelial-mesenchymal transition (EMT) is a cellular mechanism known to occur during critical phases of embryonic development [8]. Similar, yet pathophysiological transitions occur during the progression of epithelial tumors, endowing cancer cells with increased motility and invasiveness to seed metastasis [9]. Cancer cells www.impactjournals.com/oncotarget switch off the expression of epithelial markers, such as E-cadherin and catenins, and turn on mesenchymal markers, including Vimentin and fibronectin [10]
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