Cytoskeletal protein flightless I inhibits apoptosis, enhances tumor cell invasion and promotes cutaneous squamous cell carcinoma progression

// Zlatko Kopecki 1 , Gink N. Yang 1 , Jessica E. Jackson 1 , Elizabeth L. Melville 1 , Matthew P. Caley 2 , Dedee F. Murrell 3 , Ian A. Darby 4 , Edel A. O’Toole 2 , Michael S. Samuel 5 , Allison J. Cowin 1 1 Regenerative Medicine, Future Industries Institute, University of South Australia, Adelaide, South Australia, Australia 2 Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom 3 Department of Dermatology, St. George Hospital and University of New South Wales, Sydney, New South Wales, Australia 4 School of Medical Sciences, RMIT University, Melbourne, Victoria, Australia 5 Centre for Cancer Biology, an alliance between SA Pathology and the University of South Australia, Australia Correspondence to: Zlatko Kopecki, e-mail: zlatko.kopecki@unisa.edu.au Keywords: Flightless, squamous cell carcinoma, cell invasion, skin cancer Received: April 20, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT Flightless I (Flii) is an actin remodeling protein that affects cellular processes including adhesion, proliferation and migration. In order to determine the role of Flii during carcinogenesis, squamous cell carcinomas (SCCs) were induced in Flii heterozygous ( Flii +/− ), wild-type and Flii overexpressing ( Flii Tg/Tg ) mice by intradermal injection of 3-methylcholanthrene (MCA). Flii levels were further assessed in biopsies from human SCCs and the human SCC cell line (MET-1) was used to determine the effect of Flii on cellular invasion. Flii was highly expressed in human SCC biopsies particularly by the invading cells at the tumor edge. Flii Tg/Tg mice developed large, aggressive SCCs in response to MCA. In contrast Flii +/− mice had significantly smaller tumors that were less invasive. Intradermal injection of Flii neutralizing antibodies during SCC initiation and progression significantly reduced the size of the tumors and, in vitro , decreased cellular sphere formation and invasion. Analysis of the tumors from the Flii overexpressing mice showed reduced caspase I and annexin V expression suggesting Flii may negatively regulate apoptosis within these tumors. These studies therefore suggest that Flii enhances SCC tumor progression by decreasing apoptosis and enhancing tumor cell invasion. Targeting Flii may be a potential strategy for reducing the severity of SCCs.