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

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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-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).Conclusions: 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.

Original languageEnglish
Article number139
JournalBMC Cancer
Volume11
DOIs
Publication statusPublished - Apr 16 2011

Keywords

  • AxlPDGFR-αC-Met
  • Bladder cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

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    Yeh, C. Y., Shin, S. M., Yeh, H. H., Wu, T. J., Shin, J. W., Chang, T. Y., Raghavaraju, G., Lee, C. T., Chiang, J. H., Tseng, V. S., Lee, Y. C. G., Shen, C. H., Chow, N. H., & Liu, H. S. (2011). Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer. BMC Cancer, 11, [139]. https://doi.org/10.1186/1471-2407-11-139