Gastric cancer (GC) is a highly heterogeneous disease and one of the major causes of cancer-related mortality worldwide. Diffuse-type gastric adenocarcinoma (or poorly cohesive- with independent cells) is characterized by aggressive behavior (rapid invasion, chemoresistance and peritoneal metastasis), as compared with intestinal-subtype adenocarcinoma. Diffuse subtype GC additionally has a substantially increasing incidence rate in Europe and the USA, and was often associated with younger age. Our objective was to analyze the expression and clinical significance of genes involved in several signaling pathways in diffuse-type GC. Tumors samples and non-malignant gastric tissues were obtained from patients with GC (diffuse-type and intestinal-subtype adenocarcinoma). The expression of 33 genes coding for proteins involved in four categories, growth factors and receptors, epithelial-mesenchymal transition, cell proliferation and migration, and angiogenesis was determined by reverse transcription-quantitative polymerase chain reaction. The expression of 22 genes was significantly upregulated in diffuse-type GC and two were downregulated (including ) compared with normal tissues. Among these genes, acompared with intestinal-subtype adenocarcinoma, diffuse-type GC revealed elevated levels of and and and , and decreased levels of and . The expression of selected genes was compared with other genes and according to clinical parameters. Furthermore, expression was significantly increased in linitis, a sub-population of diffusely infiltrating type associated with extensive fibrosis and tumor invasion. Our study identified new target genes ( and ) whose expression is associated with aggressive phenotype of diffuse-type GC.