Wagh Purnima K, Peace Belinda E, Waltz Susan E
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA.
Adv Cancer Res. 2008;100:1-33. doi: 10.1016/S0065-230X(08)00001-8.
The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulating-protein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, small interfering RNA (siRNA), monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.
Ron受体是细胞表面受体酪氨酸激酶Met家族的成员，主要在上皮细胞和巨噬细胞中表达。Ron的生物学反应是由其配体肝细胞生长因子样蛋白/巨噬细胞刺激蛋白（HGFL）的结合介导的。HGFL主要作为无活性前体从肝细胞合成并分泌，在细胞表面被激活。HGFL与Ron的结合激活Ron，并导致多种细胞内信号级联反应的诱导，从而导致细胞生长、运动和侵袭。最近的研究记录了Ron在包括乳腺癌、结肠癌、肝癌、胰腺癌和膀胱癌在内的多种人类癌症中的过表达。此外，临床研究还表明，Ron过表达与患者预后较差以及转移有关。在转基因小鼠中强制过表达Ron会导致肺和乳腺发生肿瘤，并与转移扩散有关。虽然Ron过表达似乎是许多人类癌症的一个标志，但Ron诱导肿瘤发生和转移的机制仍不清楚。目前正在采取几种策略来抑制Ron作为潜在的治疗靶点；目前的策略包括使用Ron阻断蛋白、小分子干扰RNA（siRNA）、单克隆抗体和小分子抑制剂。总的来说，这些数据表明Ron是肿瘤发生的关键因素，抑制这种蛋白，单独或与目前的治疗方法联合使用，可能对癌症患者的治疗有益。
