RON is associated with tumor progression via the inhibition of apoptosis and cell cycle arrest in human gastric cancer

The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed in epithelial cancers, including gastric cancer. The aims of the present study were to evaluate whether RON affects tumor cell behaviors and oncogenic signaling pathways, and to document the relationship of its expression with various clinicopathological parameters in gastric cancer. The biological role of RON in tumor cell behaviors and oncogenic signaling pathways was investigated by using small interfering RNA in gastric cancer cell lines including AGS and MKN28. The expression of RON in gastric cancer tissues was investigated by using reverse transcription polymerase chain reaction and immunohistochemistry. Knockdown of RON suppressed tumor cell migration and invasion in AGS and MKN28, induced apoptosis through modulation of anti‐apoptotic and pre‐apoptotic genes and induced cell cycle arrest by decreasing cyclin D1, cyclin D3 and CDK4, and by inducing p21 and p27 expression. Signaling cascades, including Akt and mitogen‐activated protein kinase (MAPK), were significantly blocked by knockdown of RON. Expression of RON was significantly associated with tumor size, depth of invasion, lymph node metastasis, tumor stage and poor survival. These results indicate that RON is associated with tumor progression via the inhibition of apoptosis and cell cycle arrest in human gastric cancer.