Yeh et al. BMC Cancer 2011, 11:139 http://www.biomedcentral.com/1471-2407/11/139 R E S E A R C H A R T I C L E Open Access Transcriptional activation of the Axl and PDGFR-a by c-Met through a ras- and Src-independent mechanism in human bladder cancer Chen-Yun Yeh1, Shin-Mei Shin1, Hsuan-Heng Yeh3, Tsung-Jung Wu2, Jyh-Wei Shin4, Tsuey-Yu Chang4, Giri Raghavaraju1, Chung-Ta Lee2, Jung-Hsien Chiang5, Vincent S Tseng5, Yuan-Chii G Lee7, Cheng-Huang Shen8, Nan-Haw Chow2,6† and Hsiao-Sheng Liu1,6*† Abstract Background: A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers. Methods: Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C- Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients. Results: A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-a) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-a in vitro was through a ras- and Src-independent activation of mitogen- activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co- expression of these RTKs was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/ PDGFR-a or c-Met alone showed the most significant correlation with poor survival (p < 0.01). Conclusions: In addition to c-Met, the cross-talk with Axl and/or PDGFR-a also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-a expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy. Keywords: Axl PDGFR-α, c-Met, bladder cancer Background The RTK c-Met is expressed during normal develop- ment and plays a crucial role in many cell regulatory processes [1]. After binding to its cognate ligand-hepa- tocyte growth factor (HGF), activated c-Met transmits signals implicated in the cell proliferation, motility, sur- vival, and morphogenesis [2-4]. C-Met is over-expressed and usually associated with metastatic progression of a * Correspondence: a713@mail.ncku.edu.tw † Contributed equally 1Department of microbiology and immunology, College of medicine, National Cheng Kung University, Tainan, Taiwan Full list of author information is available at the end of the article variety of human malignant tumors, including bladder cancer [1,5]. We have reported that c-Met is over- expressed in 32.3%, 63.2%, and 65.2% of superficial, locally advanced and metastatic bladder cancer, respec- tively [6]. Over-expression of c-Met is positively asso- ciated with muscle invasion and poor long term survival (p < 0.001), while it is not related to patient outcome in the subset of superficial bladder cancer. Miyata et al. also reported the significance of c-Met in bladder cancer development and as an important predictor of metasta- sis and patient survival [7]. Therefore, c-Met is emerging as a novel therapeutic target in many solid tumors [8-10]. © 2011 Yeh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.