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

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 (FliiTg/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. FliiTg/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.

Reducing Flightless I expression decreases severity of psoriasis in an imiquimod-induced murine model of psoriasiform dermatitis

“…An in vitro study showed that Flii competes with MyD88 by binding to the TIR region of TLR4 and inhibits the formation of the TLR4/MyD88 signalling complex required for activation of cytokine secretion pathways . Flii expression in the skin is upregulated during development and in response to inflammation, tissue injury, skin cancer development and hypertrophic scarring . A recent study in an in vivo model of diabetic wound healing, showed that decreasing cutaneous Flii levels was associated with reduced inflammation and levels of TLR4 expression .…”

Mechanical Force and Actin Dynamics during Cutaneous Squamous Cell Carcinoma (cSCC) Progression: Opportunities for Novel Treatment Modalities

“…Invadopodia, unlike lamelli-and filopodia, are protrusions branching out from the sides of a cell, which have increased membrane remodeling and matrix degradation proteins [21]. These particular membrane protrusions are often seen in cancer cells including during cSCC progression [23].…”

“…Studies have shown that downregulation of gelsolin proteins counteracts cancer cell invasion in vitro [64], however in cSCC, gelsolin and Flii have been the most studied to-date. Gelsolin over-expression has been shown to promote cell growth and motility in oral SCC [64,65], while Flii, through its effects on apoptosis, has been linked to promotion of breast cancer progression and invasion and progression of cSCC [23,66]. Flii is an important regulator of cell adhesion, migration and proliferation and a number of previous studies have described the role of Flii protein in wound healing and demonstrated the therapeutic effect of Flii neutralizing antibodies (FnAb) in acute and chronic wounds, skin blistering diseases and inflammatory skin conditions [25,32,[67][68][69][70][71][72].…”

“…Flii is an important regulator of cell adhesion, migration and proliferation and a number of previous studies have described the role of Flii protein in wound healing and demonstrated the therapeutic effect of Flii neutralizing antibodies (FnAb) in acute and chronic wounds, skin blistering diseases and inflammatory skin conditions [25,32,[67][68][69][70][71][72]. Flii modulates cell adhesion and paxillin signaling, and regulates actin polymerization, tight junction formation and ECM production during wound repair suggesting that similar roles may govern Flii activity in cSCC progression [23,25,32,72]. Indeed, altering Flii levels both genetically and using Flii neutralizing antibodies significantly augments cSCC progression [23].…”

“…Flii modulates cell adhesion and paxillin signaling, and regulates actin polymerization, tight junction formation and ECM production during wound repair suggesting that similar roles may govern Flii activity in cSCC progression [23,25,32,72]. Indeed, altering Flii levels both genetically and using Flii neutralizing antibodies significantly augments cSCC progression [23]. Therapeutic approaches targeting Flii in cSCC are described in Section 4.…”