Notch refers to a set of genes encoding a family of transmembrane receptors in mammalian cells. Previous evidence indicated that Notch receptors were implicated in the onset of gastric cancer. However, there is little evidence on the different genetic expression patterns of the four Notch receptors and their values for patient prognosis. Most recently, we investigated the transcriptional data of Notch receptors and related patient survival in patients with GC based on several databases, including ONCOMINE, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER. According to our findings, gastric cancer tissues, compared with adjacent normal tissues presented a higher level of expression of Notch1/2/3. We also performed a survival analysis and noted that gastric cancer patients with high transcription levels of Notch1/2/3/4 had a low relapse-free survival. In gastric cancer patients, higher levels of infiltration in their CD4+ T cells, macrophages, neutrophils, and dendritic cells were positive associated with the expression of Notch receptors. Notch expression had significant association with diverse immune marker sets in gastric cancer. Overall, this study provides evidence that Notch1/2/3/4 could become the potential targets for precision treatment and new biomarkers in the prognosis of gastric cancer.

The GKN2 is a secretory protein, whose levels decrease in gastric cancer. The present study aimed to investigate the expression, function and mechanism of action of GKN2 in gastric cancer. Molecular biology assays were performed to elucidate the function and underlying mechanisms of GKN2 in gastric cancer under stress-induced condition in vivo and in vitro. Clinical specimens were used to assess the correlation of GKN2 and prognosis. We found that overexpression of GKN2 significantly enhanced apoptosis and growth arrest in vitro. GKN2 expression increased in gastric cancer cells exposed to hydrogen peroxide and promoted reactive oxygen species-induced mitochondrial dysfunction and resulted in increased cell apoptosis via inhibition of NF-κB signaling pathway and activation of JNK signaling pathway through the direct interaction of GKN2 with Hsc70. Trefoil factor 1 might contribute to the tumor suppressing effects of GKN2. MiR-216a downregulated GKN2 expression. GKN2 also inhibited xenograft tumor growth and was an independent and significant prognostic factor for patients with gastric cancer treated with oxaliplatin. Taken together, our data indicate that GKN2 may increase sensitivity of GC cells to the drugs which increase ROS levels in tumors. Inhibition of the interaction between GKN2 and Hsc70 could attenuate the effects induced by GKN2. GKN2 overexpression could be used to determine the subgroup of patients to obtain the more favorable outcome of oxaliplatin treatment and may be used as biomarker of the prognosis of this cancer.