title: Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.
abstract: BACKGROUND
  8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC).
  
  
  METHODS
  SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing.
  
  
  RESULTS
  High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein.
  
  
  CONCLUSIONS
  Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.
authors.forename: Antonia K
authors.initials: AK
authors.lastname: Roseweir
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.
authors.forename: Tahir
authors.initials: T
authors.lastname: Qayyum
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Lim
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK.
authors.forename: Alasdair I
authors.initials: AI
authors.lastname: MacDonald
authors.affiliation: NHS Greater Clyde and Glasgow, Southern General Hospital, G51 4TF, Glasgow, Scotland, UK.
authors.forename: Sioban
authors.initials: S
authors.lastname: Fraser
authors.affiliation: NHS Greater Clyde and Glasgow, Southern General Hospital, G51 4TF, Glasgow, Scotland, UK.
authors.forename: Grenville M
authors.initials: GM
authors.lastname: Oades
authors.affiliation: NHS Greater Clyde and Glasgow, Gartnavel Hospital, G12 0YN, Glasgow, Scotland, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Aitchison
authors.affiliation: Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 0YN, Glasgow, Scotland, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK. joanne.edwards@glasgow.ac.uk.
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D051419:Paxillin / Q000008:administration & dosage; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis; D019061:src-Family Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051419:Paxillin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000069439:Dasatinib
keywords: Apoptosis; Dasatinib; Human cell lines; Paxillin; Phosphorylation; Renal cell carcinoma; Src family kinases; Wound healing