Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers.
Recepteur d'origine nantais (RON) belongs to a subfamily of receptor tyrosine kinases (RTK) with unique expression patterns and biological activities. RON is activated by a serum-derived growth factor macrophage stimulating protein (MSP). The RON gene transcription is essential for embryonic development and critical in regulating certain physiological processes. Recent studies have indicated that altered RON expression contributes significantly to cancer progression and malignancy. In primary tumors, such as colon and breast cancers, overexpression of RON exists in large numbers and is often accompanied by the generation of different splicing variants. These RON variants direct a unique program that controls cell transformation, growth, migration, and invasion, indicating that altered RON expression has the ability to regulate motile/invasive phenotypes. These activities were also seen in transgenic mice, in which targeted expression of RON in lung epithelial cells resulted in numerous tumors with pathological features of human bronchioloalveolar carcinoma. Thus, abnormal RON activation is a pathogenic factor that transduces oncogenic signals leading to uncontrolled cell growth and subsequent malignant transformation. Considering these facts, RON and its variants can be considered as potential targets for therapeutic intervention. Experiments using small interfering RNA and neutralizing monoclonal antibodies demonstrated that suppressing RON expression and activation decreases cancer cell proliferation, increases apoptotic death, prevents tumor formation in nude mice, and reduces malignant phenotypes. Thus, blocking RON expression and activation has clinical significance in reversing malignant phenotypes and controlling tumor growth.
Wang
Ming-Hai
MH
Laboratory of Chang-Kung Scholars Program for Tumor Biology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. minghai.wang@ttuhsc.edu
Yao
Hang-Ping
HP
Zhou
Yong-Qing
YQ
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism*; D014644:Genetic Variation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases