Purpose: Collaboration of heterologous receptor tyrosine kinases has emerged as an important paradigm in tumor progression. We recently proved that RON has an important role in human bladder carcinogenesis. Since epidermal growth factor receptor has been suggested to cross-talk with RON, we examined the significance of epidermal growth factor receptor in modulating RON associated tumorigenesis. Materials and Methods: The biological significance of collaboration between RON and epidermal growth factor receptor was examined in the TSGH8301, J82 and JR bladder cancer cell lines with different expression status. Immunoprecipitation and immunoblotting assays were done to investigate the interaction of RON with epidermal growth factor receptor in relation to epidermal growth factor receptor kinase inhibitor treatment. Time lapse wound healing monitoring and Transwell™ assay were used for cell migration analysis and the effect on cell transformation was analyzed with foci formation assay. Finally, a bladder cancer cohort of 78 patients was studied for clinical significance by immunohistochemistry. Results: Epidermal growth factor receptor was directly associated with RON, irrespective of ligand stimulation. The siRNA experiment and epidermal growth factor receptor kinase inhibitors efficiently inhibited RON related biological effects, including mitogenesis, migration, anti-apoptosis and neoplastic transformation. Co-expression of RON/epidermal growth factor receptor was found in 26 of 78 patients (33.3%) with bladder cancer. It was significantly associated with tumor invasion (p <0.05), the risk of local recurrence (p = 0.0003) and decreased patient survival (p = 0.04). Important indicators for patient survival were co-expression of RON and epidermal growth factor receptor (p = 0.001) and tumor staging (p = 0.05). Conclusions: Cross-talk between epidermal growth factor receptor and RON exists in vivo. Thus, it should be considered in treatment planning for patients with bladder cancer.
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