Abstract
Collagen XVII and integrin α6β4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin α6β4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin γ2, collagen XVII and integrin β4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen’s disease. The expression of laminin γ2 was highest in SCC samples, whereas the expression of collagen XVII and integrin β4 varied greatly in SCC and its precursors. Collagen XVII and integrin β4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin β4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin β4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin β4 contribute to SCC tumorigenesis.
Highlights
Cutaneous squamous cell carcinoma (SCC) is among the most common carcinomas and its incidence has been rising rapidly over the past two decades[1]
Collagen XVII has a well-established function in keratinocyte adhesion and migration[13,14,15], it is critical for the maintenance of hair follicle stem cells[16] and it is abnormally distributed and up-regulated in actinic keratosis, Bowen’s disease, basal cell carcinomas and especially in the invasive areas of cutaneous and mucosal SCCs growth[17,18,19,20]
For quantitative analysis of patient samples, we calculated the proportion of positive immunoreaction in epithelial cells relative to total epithelial cell area in tissue microarray (TMA) samples of normal skin, actinic keratosis, Bowen’s disease and SCC (Fig. 1)
Summary
Cutaneous squamous cell carcinoma (SCC) is among the most common carcinomas and its incidence has been rising rapidly over the past two decades[1]. To clarify the relationship between these three cutaneous adhesion proteins in SCC carcinogenesis we first analyzed simultaneously the expression of collagen XVII, laminin γ2 and integrin β4 in human samples cutaneous SCC and its precursors, actinic keratosis and Bowen’s disease as well as chemically induced skin carcinomas of mice. Another focus of our work was to assess and compare the function of hemidesmosomal binding partners, collagen XVII and integrin β4, in SCC cells using viral knockdown of collagen XVII and integrin β4. Our study demonstrates a clear disturbance in migration and invasion in collagen XVII- and integrin β4-deficient SCC cells
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