puh. (08) 315 2011 (vaihde)
faksi (08) 315 3135
90014 Oulun yliopisto
Ihotautien hallintoon ja poliklinikalla löydät OYS:n sisäänkäyntien A3:1 tai A3:2 kautta.
Skin, the largest organ of our body, is composed of two layers: epidermis and dermis. The dermal-epidermal junction, the skin basement membrane zone, has proven to be an excellent biological system for studying epithelial-mesenchymal interactions and epithelial adhesion. Hemidesmosomes are multiprotein complexes (Fig. 1), which are critical to the stable connection of the cytoskeleton of epithelial cells within the basement membrane.
The main interest of our research group is collagen XVII (also known as BP180) which is a member of emerging collagenous transmembrane protein family. Collagen XVII is a transmembrane component of hemidesmosomes: its cytosolic N-terminus is incorporated into the hemidesmosomal plaque, and the extracellular domain localizes to the region of anchoring filaments within the basement membrane. The collagenous ectodomain of collagen XVII is proteolytically released from the cell surface. Collagen XVII has multiple binding partners such as laminin-5 and α6β4 integrin, and these interactions are essential for the assembly and stabilization of cutaneous anchoring complex. The importance of collagen XVII is supported by pathological skin conditions. In autoimmune diseases of the pemphigoid group, autoantibodies target collagen XVII and mutations in COL17A1 gene lead to junctional epidermolysis bullosa.
Proteolytic processing and maturation of its components is nn interesting feature in skin basement membrane biology. A wide spectrum of extracellular matrix molecules is proteolytically cleaved to yield mature biosynthetic products, and to release functionally important domains or biologically active fragments. We have shown that collagen XVII ectdomain is shed by ADAMs (a disintegrin metalloproteases) and that shedding occurs within the extracellular linker domain, NC16A, which is also required for the triple-helix formation of collagen XVII. After shedding the soluble ectodomain remains stable in the extracellular space, and it is expected to regulate the detachment, differentation and motility of keratinocytes.
The majority of COL17A1 mutations are homozygous or heterozygous nonsense mutations, or small insertions or deletions, resulting in premature termination codon and absence of collagen XVII in the skin. In contrast, there are only a few patients with missense mutations or deletions. In collaboration with the research group of Professor Leena Bruckner-Tuderman (University of Freiburg, Germany) we have found novel missense mutations and deletions and analyzed their consequences to the structure and function of collagen XVII by using mutated recombinant full-length collagen XVII. We have shown that glycine substitution mutations in the largest collagenous domain of collagen XVII significantly decrease the thermal stability of the whole ectodomain. In addition, we demonstrated that a large C-terminal deletion impairs the glycosylation of collagen XVII and leads to intracellular accumulation of mutated polypeptide. Taken together, our results have brought a lot of valuable information about the molecular mechanisms of junctional EB.
Squamous cell carcinoma (SCC) is a malignant epithelial tumor which usually arises from premalignant skin lesions. In Finland, about 1000 new cutaneous SCCs are diagnosed every year. The development and progression of SCC is a complex and multistage process, which is controlled by interactions of neighboring host cells and variety of microenviromental factors. Before SCC cells can invade, they must adhere and migrate through the surrounding extracellular matrix (ECM). It is well accepted that the two ECM components and ligands of collagen XVII, laminin-5 and α6β4 integrin, are essential for the genesis of invasive SCC cells. We have previously shown that collagen XVII is up-regulated in dysplasias of oral mucosa and in tongue SCCs, and that collagen XVII is expressed by SCC cells at higher levels than in normal keratinocytes. Increased collagen XVII expression was detected in areas of invasive front suggesting a correlation between overexpression and invasive potential of collagen XVII. Moreover, we were able to demonstrate that the cell adhesion domain of collagen XVII, Col15, is able chemotactically to attract invasive HSC-3 SCC cells through α6β4, αv, and αIIb integrin receptors.
In addition to skin, collagen XVII is expressed in epithelial cells of buccal mucosa, upper oesophagus, bladder, retina, ocular cornea and conjunctiva. We have recently shown in co-ordination with another research group that neurons of central nervous system also express collagen XVII. Our on-going project demonstrates that cytotrophoblast and extravillous trophoblastic cells of human placenta and epithelial cells of human amnion express collagen XVII. In this study we also analyzed regulation and biochemical characteristics of collagen XVII in these cells. We are currently using immortalized extravillous trophoblastic cells as an invasive model to study premigratory effects of collagen XVII.
The long-term aim of our research projects is to understand better the function of collagen XVII in the adhesion and migration of epithelial cells and their interaction with connective tissue stroma. Another aim is to study the role of collagen XVII in SCC tumorigenesis, and especially try to understand how is collagen XVII overexpression related to increased migratory potential of SCC cells. This may lead to development of new diagnostic tools for tumor invasiveness and patient prognosis.
Kaisa Tasanen-Määttä, M.D., Ph.D., clinical lecturer
Tiina Hurskainen, Ph.D.
Laura Huilaja, M.D.
Jyri Moilanen, medical student