1. Increased expression of flightless I in cutaneous squamous cell carcinoma affects wnt/β-catenin signaling pathway
- Author
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Gink N. Yang, Xanthe L. Strudwick, Claudine S. Bonder, Zlatko Kopecki, Allison J. Cowin, Yang, Gink N, Strudwick, Xanthe L, Bonder, Claudine S, Kopecki, Zlatko, and Cowin, Allison J
- Subjects
squamous cell carcinoma ,Skin Neoplasms ,QH301-705.5 ,Flightless ,Article ,Catalysis ,Inorganic Chemistry ,Mice ,Cell Line, Tumor ,cancer metastasis ,Animals ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Wnt Signaling Pathway ,Molecular Biology ,QD1-999 ,Spectroscopy ,Cell Proliferation ,Microfilament Proteins ,Organic Chemistry ,General Medicine ,non-melanoma skin cancer ,Up-Regulation ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Chemistry ,Gene Knockdown Techniques ,flightless ,Carcinoma, Squamous Cell ,Trans-Activators ,Female ,Methylcholanthrene - Abstract
Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in Caucasian populations. Surgical removal in combination with radiation and chemother-apy are effective treatments for cSCC. Nevertheless, the aggressive metastatic forms of cSCC still have a relatively poor patient outcome. Studies have linked actin cytoskeletal dynamics and the Wnt/β-catenin signaling pathway as important modulators of cSCC pathogenesis. Previous studies have also shown that the actin-remodeling protein Flightless (Flii) is a negative regulator of cSCC. The aim of this study was to investigate if the functional effects of Flii on cSCC involve the Wnt/β-catenin signaling pathway. Flii knockdown was performed using siRNA in a human late stage aggressive metastatic cSCC cell line (MET-1) alongside analysis of Flii genetic murine models of 3-methylcholanthrene induced cSCC. Flii was increased in a MET-1 cSCC cell line and reducing Flii expression led to fewer PCNA positive cells and a concomitant reduction in cellular proliferation and symmetrical division. Knockdown of Flii led to decreased β-catenin and a decrease in the expression of the downstream effector of β-catenin signaling protein SOX9. 3-Methylcholanthrene (MCA)-induced cSCC in Flii overexpressing mice showed increased markers of cancer metastasis in-cluding talin and keratin-14 and a significant increase in SOX9 alongside a reduction in Flii associated protein (Flap-1). Taken together, this study demonstrates a role for Flii in regulating proteins involved in cSCC proliferation and tumor progression and suggests a potential role for Flii in aggressive metastatic cSCC. Refereed/Peer-reviewed
- Published
- 2021