Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Pathol Int. 2012 Feb;62(2):127-36. doi: 10.1111/j.1440-1827.2011.02765.x. Epub 2011 Nov 28.
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.
纳坦起源受体（RON）受体酪氨酸激酶在包括胃癌在内的上皮性癌中过度表达。本研究旨在评估 RON 是否影响肿瘤细胞行为和致癌信号通路，并记录其在胃癌中的表达与各种临床病理参数的关系。通过使用小干扰 RNA 在胃癌细胞系 AGS 和 MKN28 中研究 RON 在肿瘤细胞行为和致癌信号通路中的生物学作用。通过逆转录聚合酶链反应和免疫组织化学研究 RON 在胃癌组织中的表达。RON 的敲低抑制了 AGS 和 MKN28 中的肿瘤细胞迁移和侵袭，通过调节抗凋亡和凋亡前基因诱导细胞凋亡，并通过降低细胞周期蛋白 D1、D3 和 CDK4 以及诱导 p21 和 p27 表达诱导细胞周期停滞。包括 Akt 和丝裂原活化蛋白激酶（MAPK）在内的信号级联反应被 RON 的敲低显著阻断。RON 的表达与肿瘤大小、浸润深度、淋巴结转移、肿瘤分期和预后不良显著相关。这些结果表明，RON 通过抑制人类胃癌中的细胞凋亡和细胞周期停滞与肿瘤进展相关。
