Wang Ming-Hai, Wang Da, Chen Yi-Qing
Laboratory of Chang-Jiang Scholar Endowment for Biomedical Sciences, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, Peoples Republic of China.
Carcinogenesis. 2003 Aug;24(8):1291-300. doi: 10.1093/carcin/bgg089. Epub 2003 May 22.
The product of the RON (recepteur d'origine nantais) gene belongs to the MET proto-oncogene family, a distinct subfamily of receptor tyrosine kinases. The ligand of RON was identified as macrophage-stimulating protein (MSP), a member of the plasminogen-related growth factor family. RON is mainly expressed in cells of epithelial origin and is required for embryonic development. In vitro RON activation results in epithelial cell dissociation, migration and matrix invasion, suggesting that RON might be involved in the pathogenesis of certain epithelial cancers in vivo. Indeed, recent studies have shown that RON expression is significantly altered in several primary human cancers, including those of the breast and colon. Truncation of the RON protein has also been found in primary tumors from the gastrointestinal tract. These alterations lead to constitutive activation of RON that causes cell transformation in vitro, induces neoplasm formation in athymic nude mice, and promotes tumor metastasis into the lung. Studies employing transgenic models further demonstrated that over-expression of RON in lung epithelial cells results in multiple tumor formation with features of large cell undifferentiated carcinoma. The oncogenic activities of RON are mediated by RON-transduced signals that promote unbalanced cell growth and transformation leading to tumor development. Thus, abnormal accumulation and activation of RON could play a critical role in vivo in the progression of certain malignant human epithelial cancers.
RON（源自南特的受体）基因的产物属于MET原癌基因家族，是受体酪氨酸激酶的一个独特亚家族。RON的配体被确定为巨噬细胞刺激蛋白（MSP），它是纤溶酶原相关生长因子家族的成员。RON主要在上皮来源的细胞中表达，是胚胎发育所必需的。在体外，RON激活会导致上皮细胞解离、迁移和基质侵袭，这表明RON可能在体内某些上皮癌的发病机制中起作用。事实上，最近的研究表明，RON的表达在几种原发性人类癌症中显著改变，包括乳腺癌和结肠癌。在胃肠道的原发性肿瘤中也发现了RON蛋白的截短。这些改变导致RON的组成性激活，在体外引起细胞转化，在无胸腺裸鼠中诱导肿瘤形成，并促进肿瘤转移到肺部。采用转基因模型的研究进一步证明，肺上皮细胞中RON的过度表达会导致具有大细胞未分化癌特征的多个肿瘤形成。RON的致癌活性由RON转导的信号介导，这些信号促进不平衡的细胞生长和转化，导致肿瘤发展。因此，RON的异常积累和激活可能在体内某些人类恶性上皮癌的进展中起关键作用。
