NRAGE confers poor prognosis and promotes proliferation, invasion, and chemoresistance in gastric cancer.

Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) is a type II melanoma-associated antigen that plays an essential role in various processes, including cell differentiation and apoptosis. NRAGE has been shown to act as a cancer-related protein, with complex and apparently contradictory functions in a variety of cancers. In the current study, we examined the expression of NRAGE protein in 169 gastric cancer samples. NRAGE upregulation was correlated with advanced TNM stage, local invasion, and poor survival. Importantly, NRAGE could serve as an independent prognostic factor in patients with gastric cancer. We also examined the expression of NRAGE protein in GES-1 normal gastric epithelial cells and in six gastric cancer cell lines. Inhibition of NRAGE expression by transfection with small interfering RNA reduced the proliferation and invasion of MGC-803 and HGC-27 cells, as demonstrated by CCK-8 and Matrigel invasion assays. NRAGE depletion also sensitized HGC-27 and MGC-803 cells to cisplatin, as shown by CCK-8 and Annexin V/propidium iodide analyses. Western blot analysis also showed that NRAGE depletion negatively regulated Bcl-2 and p-ERK and upregulated ZO-1 and p27 expression levels. In conclusion, our results suggest that NRAGE acts as a tumor promoter in gastric cancer by facilitating cancer invasion and chemoresistance, possibly through regulation of p-ERK and Bcl-2.