title: Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer.
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.
authors.affiliation: Department of microbiology and immunology, College of medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chen-Yun
authors.initials: CY
authors.lastname: Yeh
authors.forename: Shin-Mei
authors.initials: SM
authors.lastname: Shin
authors.forename: Hsuan-Heng
authors.initials: HH
authors.lastname: Yeh
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Wu
authors.forename: Jyh-Wei
authors.initials: JW
authors.lastname: Shin
authors.forename: Tsuey-Yu
authors.initials: TY
authors.lastname: Chang
authors.forename: Giri
authors.initials: G
authors.lastname: Raghavaraju
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.forename: Jung-Hsien
authors.initials: JH
authors.lastname: Chiang
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tseng
authors.forename: Yuan-Chii G
authors.initials: YC
authors.lastname: Lee
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Shen
authors.forename: Nan-Haw
authors.initials: NH
authors.lastname: Chow
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013752:Tetracycline / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000503:physiopathology*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D015688:Oncogene Protein pp60(v-src); D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras); D013752:Tetracycline; D000094963:Axl Receptor Tyrosine Kinase