EPHA2/EFNA1 expression in human gastric cancer

Abstract

The erythropoietin-producing hepatocellular (EPH)A2 receptor, tyrosine kinase, is overexpressed and phosphorylated in several types of human tumors and has been associated with malignant transformation. A recent report, however, indicated that stimulation of the EPHA2 receptor ligand, ephrinA1 (EFNA1), inhibits the growth of EPHA2-expressing breast cancer. The authors examined the expression of EPHA2 and EFNA1 using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in four gastric cancer cell lines and 49 primary gastric cancer samples, as well as in normal gastric tissue. EPHA2 was more highly expressed in tumor tissue than in normal tissue in 27 cases (55%). EFNA1 was overexpressed in tumor tissue in 28 cases (57%). No significant correlation was detected between the expression levels and histologic features such as tumor size, age, vessel invasion, or lymph node involvement. However, EPHA2 overexpression was more prominent in macroscopic type 3 and 4 tumors than in type 1 or 2 advanced gastric cancer. The authors observed EPHA2 expression in three of the four gastric cancer cell lines (AGS, KATO3, and MKN74) that were examined. In one cell line, TMK1, EPHA2 expression was barely detectable using northern blotting, RT-PCR, and western blotting. In contrast, EFNA1 was detected in all cell lines. In the gastric cancer cell lines that endogenously expressed EPHA2, stimulation with ephrinA1-Fc led to decreased EPHA2 protein expression and increased EPHA2 phosphorylation. Finally, the growth of T he erythropoietin-producing hepatocellular (EPH ) receptors represent the largest known family of receptor tyrosine kinases and are activated by interaction with the cell-surface ligands, ephrins (EFN). There is evidence to suggest that some members of the EPH family and their EFN ligands are involved in angiogenesis and oncogenesis through cell adhesion, morphogenesis, capillary sprouting, and chemoattraction.(1−5) EPH receptors have been classified into two subfamilies, EPHA and EPHB. EPHA receptors bind mainly to glycosylphosphatidylinositolanchored EFNA ligands, and EPHB receptors bind to transmembrane EFNB ligands. The expression of EPH family transcripts has been documented in some melanomas and carcinomas.(6,7) Overexpression of EPHA2 is believed to be sufficient to confer malignant/tumorigenic potential on nontransformed mammary epithelial cells.(8) Esophageal squamous cell carcinomas that overexpress EFNA2 have a poorer prognosis than those that do not. (9)

Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis

“…The Eph family was initially known as a putative oncogene based on their overexpression in certain types of human cancers. The EphA2 receptor is overexpressed in colorectal, 24 gastric, 25 ovarian, 11 and esophageal squamous-cell carcinoma. 26 The EphA4 receptor is overexpressed in pancreatic ductal adenocarcinoma, 27 and Ephrin B1 is overexpressed in ovarian carcinoma.…”

Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

“…These receptor-ligand systems are involved in cell-cell repulsion and attraction and play a role in tissue patterning, neuronal targeting, and angiogenesis during embryonic development (17)(18)(19)(20). In addition, EphA2 overexpression has been reported in many cancers including those of the breast, lung, esophagus, stomach, cervix, ovary, colon, prostate, kidney, and skin (21)(22)(23)(24)(25)(26)(27)(28)(29). Overexpression of EphA2 has been correlated with increased metastatic potential and decreased survival (22-24, 27, 29).…”

Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

“…Generally, the upregulation of Eph/ ephrin has been reported in various types of cancer [7][8][9][10] . Overexpression of EphB2, ephrinB1, EphA2, and ephrinA1 has been reported in gastric cancer [11][12][13] . On the other hand, the concept that Eph receptors are oncogenes needs a new look on the basis of recent findings of downregulation of Eph receptors in certain types of cancer [14][15][16][17] .…”