RESUMO
Mutations in the gene encoding collagen VII cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and nonhealing wounds aggravated by scarring and fibrosis. We previously showed that TSP1 is increased in RDEB fibroblasts. Because transforming growth factor-ß (TGF-ß) signaling is also increased in RDEB, and TSP1 is known to activate TGF-ß, we investigated the role of TSP1 in TGF-ß signaling in RDEB patient cells. Knockdown of TSP1 reduced phosphorylation of smad3 (a downstream target of TGF-ß signaling) in RDEB primary fibroblasts, whereas overexpression of collagen VII reduced phosphorylation of smad3. Furthermore, inhibition of TSP1 binding to the LAP/TGF-ß complex decreased fibrosis in engineered extracellular matrix formed by RDEB fibroblasts, as evaluated by picrosirius red staining and analyses of birefringent collagen fibrillar deposits. We show that collagen VII binds TSP1, which could potentially limit TSP1-LAP association and subsequent TGF-ß activation. Our study suggests a previously unreported mechanism for increased TGF-ß signaling in the absence of collagen VII in RDEB patient skin. Moreover, these data identify TSP1 as a possible target for reducing fibrosis in the tumor-promoting dermal microenvironment of RDEB patients.
Assuntos
Epidermólise Bolhosa Distrófica/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Pele/patologia , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Criança , Pré-Escolar , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Feminino , Fibroblastos/patologia , Fibrose , Técnicas de Silenciamento de Genes , Genes Recessivos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fosforilação , Ligação Proteica , Transdução de Sinais , Proteína Smad3/metabolismo , Trombospondina 1/genética , Microambiente Tumoral , Adulto JovemRESUMO
Squamous cell carcinoma (SCC) represents one of the most frequently diagnosed tumours and contributes significant mortality worldwide. Recent deep sequencing of cancer genomes has identified common mutations in SCC arising across different tissues highlighting perturbation of squamous differentiation as a key event. At the same time significant data have been accumulating to show that common tumour-stroma interactions capable of driving disease progression are also evident when comparing SCC arising in different tissues. We and others have shown altered matrix composition surrounding SCC can promote tumour development. This review focuses on some of the emerging data with particular emphasis on SCC of head and neck and skin with discussion on the potential tumour suppressive properties of a normal microenvironment. Such data indicate that regardless of the extent and type of somatic mutation it is in fact the tumour context that defines metastatic progression.
Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Microambiente Tumoral/genética , Carcinoma de Células Escamosas/patologia , Matriz Extracelular/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Genoma Humano , Humanos , MutaçãoRESUMO
Type VII collagen is the main component of anchoring fibrils, structures that are integral to basement membrane homeostasis in skin. Mutations in the gene encoding type VII collagen COL7A1 cause recessive dystrophic epidermolysis bullosa (RDEB) an inherited skin blistering condition complicated by frequent aggressive cutaneous squamous cell carcinoma (cSCC). OATP1B3, which is encoded by the gene SLCO1B3, is a member of the OATP (organic anion transporting polypeptide) superfamily responsible for transporting a wide range of endogenous and xenobiotic compounds. OATP1B3 expression is limited to the liver in healthy tissues, but is frequently detected in multiple cancer types and is reported to be associated with differing clinical outcome. The mechanism and functional significance of tumour-specific expression of OATP1B3 has yet to be determined. Here, we identify SLCO1B3 expression in tumour keratinocytes isolated from RDEB and UV-induced cSCC and demonstrate that SLCO1B3 expression and promoter activity are modulated by type VII collagen. We show that reduction of SLCO1B3 expression upon expression of full-length type VII collagen in RDEB cSCC coincides with acquisition of front-to-rear polarity and increased organisation of 3D spheroid cultures. In addition, we show that type VII collagen positively regulates the abundance of markers implicated in cellular polarity, namely ELMO2, PAR3, E-cadherin, B-catenin, ITGA6 and Ln332.