Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer
- Equal contributors
1 Department of microbiology and immunology, College of medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of pathology, College of medicine, National Cheng Kung University, Tainan, Taiwan
3 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
4 Department of parasitology, College of medicine, National Cheng Kung University, Tainan, Taiwan
5 Department of computer science and information engineering, National Cheng Kung University, Tainan, Taiwan
6 Center for gene regulation and signal transduction research, National Cheng Kung University, Tainan, Taiwan
7 Graduate Institute of Medical Informatics, Taipei Medical University, Taipei, Taiwan
8 Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
BMC Cancer 2011, 11:139 doi:10.1186/1471-2407-11-139Published: 16 April 2011
A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.
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.
A 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).
In 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.