EphA8 acts as an oncogene and contributes to poor prognosis in gastric cancer via regulation of ADAM10

Abstract

EphA8 is a member of the erythropoietin-producing hepatocellular receptor (Eph) family of receptor tyrosine kinases. Ephs and their ephrins ligands play crucial roles in many cellular processed by mediating intracellular signaling resulting from cell-cell interactions. But the underlying mechanisms of EphA8 in gastric cancer (GC) remains unclearly. 298 clinical specimens in tissues microarray, and was found to be significantly higher in GC tissues compared with nontumor tissues (p < 0.001). EphA8 expression was also strongly associated with differentiation level (p = 0.025), tumornode-metastasis stage (p = 0.019), and poor 5 years survival (p < 0.001). A panel of GC cell lines showed reduced proliferation, invasion, and migration capacities after RNAmediated knockdown of EphA8, concomitant with downregulation of the proliferation-related proteins (cyclin A, cyclin D1, and cyclin-dependent kinase 4) and the metastasis-related (matrix metalloproteinases MMP2, and MMP9). EphA8 knockdown also decreased expression of the protease ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM10-related protein AKT, suggesting an interaction between EphA8 and ADAM10. In conclusion, we found that EphA8, which is highly expressed in GC tissues, stimulates proliferation, invasion, and migration of cancer cells, and is an independent risk factor for poor prognosis of GC.These dates suggest that EphA8 could be new diagnostic and/or therapeutic targets for GC.

ADAM10 expression in gastric adenocarcinoma: Results of a curative gastrectomy cohort

“…There are studies in the literature reporting cytoplasmic staining. 7,12,18 Although we did not compare the significance of cytoplasmic staining with the significance of membranous or nuclear staining in the present study, we think that comparison of the staining patterns may also provide useful information. Finally, there is no consensus on how to score ADAM10 expressions in the literature.…”

“…5,6 EphA8, an oncogene, has been shown to induce tumor cell proliferation and migration by increasing ADAM10 expression in gastric cancer cells. 7 Ge et al have reported that expression of microRNA-320a is inversely correlated with mRNA levels of ADAM10 and that upregulation of microRNA-320a decreases ADAM10 expression, and therefore, cell proliferation, and increases sensitivity to cisplatin in gastric cancer cells. The authors have suggested that potential therapeutic strategies for gastric carcinoma may be based on the miR-320a/ADAM10 axis.…”

Stem-like Cells from Invasive Breast Carcinoma Cell Line MDA-MB-231 Express a Distinct Set of Eph Receptors and Ephrin Ligands

“…Although the role of EPHA8 in cancer stem cells remains elusive, its overexpression correlates to a poor overall survival in other human malignancies, such as epithelial ovarian cancer (EOC) (24)(25)(26). In EOC, both EPHA8 and ephrin-A5 are significantly up-regulated (24), while only EPHA8 was reported to be overexpressed in OTSCC and GC (25).…”

“…Moreover, miR-10a mediates glioma cell migration and invasion by negatively regulating EphA8 to induce EMT (32). Although no data regarding the involvement of EPHA8 signaling in breast cancer stem-like cells is available, it is known to alter the expression of cell-cycle regulatory proteins, matrix metalloproteinases, AKT pathway (26), PI-3 kinase pathway (33), and sustained MAPK activation (34). Based on significant alteration in EphA8/ephrin-A5 abundance, we hypothesize that either EPHA8 mediates cancer stem cells transition from quiescent to proliferative state in the milieu of MDA-MB-231 environment or alternatively its constitutive expression in stem cells transforms stem cells as well as the bulk cells.…”

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

“…Notably, EPHA8-mediated inhibition of cell migration does require EPHA8 kinase activity [179]. Proliferation, migration, and invasion of gastric cancer cells are associated with EPHA8 kinase-mediated signaling involving the ADAM10 protein and downstream serine/threonine kinase AKT pathways [180]. Increased EPHA8 expression also associates with increased clinicopathological features or poor prognoses in oral tongue squamous cell carcinoma [181], colorectal cancer [182], and ovarian cancer [183].…”