Overexpression of EphA2 correlates with epithelial–mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients

Abstract

The expression of EphA2 and three epithelial-mesenchymal transition-related proteins (E-cadherin, β-catenin and vimentin) was detected by immunohistochemistry in human gastric cancer and normal gastric mucosa. The expression of EphA2 and vimentin was significantly higher in gastric cancer tissues than in normal gastric mucosa tissues, and similar results were found for negative E-cadherin expression and ectopic β-catenin expression. Further analysis showed that the expression of EphA2 was closely correlated with the depth of tumor invasion, tumor-node-metastasis (TNM) stages and lymph node metastasis. Down-regulated expression of the epithelial protein E-cadherin, overexpression of the mesenchymal protein vimentin and ectopic expression of β-catenin were associated with the depth of tumor invasion, tumor differentiation, TNM stages and lymph node metastasis. The Spearman rank test indicated that the positive expression of EphA2 was negatively associated with E-cadherin expression and was positively correlated with β-catenin ectopic expression and vimentin expression. In addition, the Kaplan-Meier survival analysis showed that the overexpression of EphA2 and vimentin, ectopic expression of β-catenin and down-regulation of E-cadherin indicate a poor outcome. Moreover, multivariate Cox analysis showed that TNM stages, lymph node metastasis, EphA2 expression, E-cadherin expression and β-catenin ectopic expression were independent prognostic factors for postoperative gastric cancer. These findings indicate that the overexpression of EphA2 correlates with the loss of epithelial proteins and the appearance of mesenchymal proteins. Therefore, EphA2 may play a role in epithelial-mesenchymal transition in gastric cancer.

The Value of HER2 neu and EphA2 expressions in Gastric Adenocarcinoma Prognosis

“…EPHA2 is overexpressed in a wide range of cancers and is associated with poor prognosis [25]. Many recent studies investigated the RTKs such as EphA2 and reported them as targets for molecular therapy for GAC [26][27][28][29], and also proved that EphA2 overexpression was positively correlated with factors that controlled angiogenesis and invasion in cancer cells because EphA2 receptor activation allowed vascular endothelial growth factor (VEGF)-dependent endothelial cell transport, sprouting, survival and expression of metalloproteinase, and these may be the causes of the poor clinical outcome of cancer patients with EphA2 overexpression, moreover the EphA2-EphrinA1 signaling axis regulates many steps that are essential for carcinogenesis and stimulation of downstream molecules like the phosphatidyl inositol 3' kinases (PI3K), mitogen activated protein kinases (MAPK) and integrins along with epidermal growth factor receptor(EGFR) that regulate cell adhesion, cancer cell growth, metastases and development of vascular network.…”

High EphA2 protein expression in renal cell carcinoma is associated with a poor disease outcome

“…Consistent with a previous study in lung carcinoma (15), the present results support EphA2 expression as an important index of disease progression. As EphA2 can be highly expressed in a broad range of cancer types (20–22), the prognostic utility of this marker may prove significant in the monitoring and clinical management of a large cohort of cancer patients.…”

The role of EPH receptors in cancer-related epithelial-mesenchymal transition

“…For instance, TGF-β activates other EMT-related signaling pathways, such as Notch, Wnt/β-catenin, and integrin[10]. Recently, a number of studies including ours have suggested that EPH receptors play a role in the EMT process[26]–[28]. However, the mechanism by which EPH receptors regulate EMT is still largely unknown.…”

“…Recently, EPH receptors have been found to play an important role in many aspects of EMT[26]–[28], including induction of a mesenchymal-like phenotype (e.g., an E-cadherin–negative and vimentin-positive phenotype) and inhibition of epithelial characteristics (e.g., an E-caherin-positive and vimentin-negative phenotype)[46]. Moreover, EPH receptors crosstalk with EMT-related signal transduction pathways such as those induced by NF-κB and PI3K[54],[55].…”

“…For example, EPHA2 is overex-pressed in gastric and colorectal cancers exhibiting liver metastasis and lymphatic vessel invasion, whereas the expression levels of E-cadherin are inversely associated with cancer stage and lymphatic vessel invasion[26],[27],[57]. Nevertheless, simultaneous expression of E-cadherin and EPHB3 was significantly inversely associated with the stage of esophageal adenocarcinoma[58], indicating that EPHB3 is a tumor suppressor gene.…”