title: Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells.
abstract: OBJECTIVE
  Fyn is a member of the Src family of kinases that we have previously shown to be overexpressed in prostate cancer. This study defines the biological impact of Fyn inhibition in cancer using a PC3 prostate cancer model.
  
  
  METHODS
  Fyn expression was suppressed in PC3 cells using an shRNA against Fyn (PC3/FYN-). Knockdown cells were characterized using standard growth curves and time-lapse video microscopy of wound assays and Dunn Chamber assays. Tissue microarray analysis was used to verify the physiologic relevance of the HGF/MET axis in human samples. Flank injections of nude mice were performed to assess in vivo growth characteristics.
  
  
  RESULTS
  HGF was found to be sufficient to drive Fyn-mediated events. Compared to control transductants (PC3/Ctrl), PC3/FYN- showed a 21% decrease in growth at 4 days (P = 0.05). PC3/FYN- cells were 34% longer than control cells (P = 0.018) with 50% increase in overall surface area (P < 0.001). Furthermore, when placed in a gradient of HGF, PC3/FYN- cells showed impaired directed chemotaxis down an HGF gradient in comparison to PC3/Ctrl (P = 0.001) despite a 41% increase in cellular movement speed. In vivo studies showed 66% difference of PC3/FYN- cell growth at 8 weeks using bidimensional measurements (P = 0.002).
  
  
  CONCLUSIONS
  Fyn plays an important role in prostate cancer biology by facilitating cellular growth and by regulating directed chemotaxis-a key component of metastasis. This finding bears particular translational importance when studying the effect of Fyn inhibition in human subjects.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Section of Urology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Jensen
authors.forename: Saito Y
authors.initials: SY
authors.lastname: David
authors.forename: Chuanhong
authors.initials: C
authors.lastname: Liao
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: Kelly
authors.initials: K
authors.lastname: Dakin-Haché
authors.forename: Peter
authors.initials: P
authors.lastname: Usatyuk
authors.forename: Margarit F
authors.initials: MF
authors.lastname: Sievert
authors.forename: Gladell P
authors.initials: GP
authors.lastname: Paner
authors.forename: Soheil
authors.initials: S
authors.lastname: Yala
authors.forename: Gustavo M
authors.initials: GM
authors.lastname: Cervantes
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018523:Tropism / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C066855:HGF protein, human; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn