Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

Chen-Yun Yeh,Jyh-Wei Shin,Nan-Haw Chow,Vincent S Tseng,Tsung-Jung Wu,Shin-Mei Shin,Cheng-Huang Shen,Hsiao-Sheng Liu,Giri Raghavaraju,Chung-Ta Lee,Yuan-Chii G Lee,Jung-Hsien Chiang,Hsuan-Heng Yeh,Tsuey-Yu Chang

doi:10.1186/1471-2407-11-139

Abstract

BackgroundA cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.MethodsBoth 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.ResultsA positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α) 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-α 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-α or c-Met alone showed the most significant correlation with poor survival (p < 0.01).ConclusionsIn addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.

Highlights

A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers
We have reported that c-Met is overexpressed in 32.3%, 63.2%, and 65.2% of superficial, locally advanced and metastatic bladder cancer, respectively [6]
It is interesting to note that c-Met or p-Met was not expressed in NIH-Met5 cells when treated with Tet alone or combined with hepatocyte growth factor (HGF) treatment (Figure 1A, lanes 5 and 6; Additional file 1, lanes 8-9)

Summary

Introduction

A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers. The RTK c-Met is expressed during normal development and plays a crucial role in many cell regulatory processes [1]. In addition to heterodimeric complex formation of the same subfamily [6,11,12,13,14], heterologous RTK interaction is involved in the pathogenesis of human cancers, e.g. between EGFR and RON (a member of the cMet family) [15,16]. In our prior RTK profiling experiment, c-Met was frequently co-expressed with Axl, platelet-derived growth factor receptor a (PDGFR-a), DDR2 and/or IGF1R in the same uroepithelial cells [17], suggesting the existence of yet unspecified cross-talk partners of c-Met

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