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

Roseweir, A. K. , Qayyum, T., Lim, Z., Hammond, R., MacDonald, A. I., Fraser, S., Oades, G. M., Aitchison, M., Jones, R. J. and Edwards, J. (2016) Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients. BMC Cancer, 16, p. 229. (doi: 10.1186/s12885-016-2254-9) (PMID:26984511) (PMCID:PMC4794832)

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 (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. 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.

• Item Type: Articles
• Additional Information: This work was supported by the Renal Cancer Research Fund Scotland and NHS Greater Clyde & Glasgow Endowment Fund (2012REN03).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Roseweir, Dr Antonia and Qayyum, Dr Tahir and Jones, Professor Robert and Edwards, Professor Joanne and Aitchison, Mr Michael and MacDonald, Dr Alasdair
• Authors: Roseweir, A. K., Qayyum, T., Lim, Z., Hammond, R., MacDonald, A. I., Fraser, S., Oades, G. M., Aitchison, M., Jones, R. J., and Edwards, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: BMC Cancer
• Publisher: BioMed Central Ltd.
• ISSN: 1471-2407
• ISSN (Online): 1471-2407
• Copyright Holders: Copyright © 2016 Roseweir et al.
• First Published: First published in BMC Cancer 16:229
• Publisher Policy: Reproduced under a Creative Commons licence