Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

BMC Cancer

Research Article

Robert J. Jones¹  Michael Aitchison²  Grenville M. Oades³  Sioban Fraser³  Tahir Qayyum⁴  Rachel Hammond⁴  Antonia K. Roseweir⁴  Zhi Lim⁴  Joanne Edwards⁴  Alasdair I. MacDonald⁴ 

[1] 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;NHS Greater Clyde and Glasgow, Gartnavel Hospital, G12 0YN, Glasgow, Scotland, UK;NHS Greater Clyde and Glasgow, Southern General Hospital, G51 4TF, Glasgow, Scotland, UK;Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G61 1QH, Glasgow, Scotland, UK;

关键词: Renal cell carcinoma;    Src family kinases;    Paxillin;    Dasatinib;    Apoptosis;    Phosphorylation;    Wound healing;    Human cell lines;   

DOI  :  10.1186/s12885-016-2254-9

 received in 2015-05-27, accepted in 2016-03-08,  发布年份 2016

来源: Springer

【 摘 要 】

Background8000 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).MethodsSFKs 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.ResultsHigh 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 (Y419) and FAK (Y861) 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Roseweir et al. 2016