ST14

Abstract: Matriptase/MT-SP1 is a novel tumor-associated type II transmembrane serine protease that is highly expressed in the epidermis, thymic stroma, and other epithelia. A null mutation was introduced into the Matriptase/MT-SP1 gene of mice to determine the role of Matriptase/MT-SP1 in epidermal development and neoplasia. Matriptase/MT-SP1-deficient mice developed to term but uniformly died within 48 h of birth. All epidermal surfaces of newborn mice were grossly abnormal with a dry, red, shiny, and wrinkled appearance. Matriptase/MT-SP1-deficiency caused striking malformations of the stratum corneum, characterized by dysmorphic and pleomorphic corneocytes and the absence of vesicular bodies in transitional layer cells. This aberrant skin development seriously compromised both inward and outward epidermal barrier function, leading to the rapid and fatal dehydration of Matriptase/MT-SP1-deficient pups. Loss of Matriptase/MT-SP1 also seriously affected hair follicle development resulting in generalized follicular hypoplasia, absence of erupted vibrissae, lack of vibrissal hair canal formation, ingrown vibrissae, and wholesale abortion of vibrissal follicles. Furthermore, Matriptase/MT-SP1-deficiency resulted in dramatically increased thymocyte apoptosis, and depletion of thymocytes. This study demonstrates that Matriptase/MT-SP1 has pleiotropic functions in the development of the epidermis, hair follicles, and cellular immune system.

Abstract: Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1–deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH2-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation.

Abstract: Purpose : Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of ovarian cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase, and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), in epithelial ovarian cancer and to assign clinicopathological correlations. Experimental Design : We have determined by immunohistochemistry the expression of matriptase and HAI-1 in 54 epithelial ovarian cancers. Statistical analyses of immunohistochemistry expression data with clinical outcome and clinicopathological parameters were then performed. Results : Of 54 tumors tested, 39 (72%) and 11 (20%) were positive for matriptase and for HAI-1, respectively. All HAI-1-positive tumors were also matriptase positive. Analysis of clinicopathological parameters demonstrated a loss of matriptase associated with stage III/IV tumors as compared with stage I/II tumors ( P = 0.030). There was also a loss of HAI-1 expression associated with stage III/IV tumors ( P = 0.039). Of 34 stage I/II tumors, 28 (82%) stained positive for matriptase, and 10 (29%) stained positive for HAI-1; 10 (29%) tumors showed coexpression. Of 20 stage III/IV tumors, however, 11 stained positive for matriptase (55%), only 1 of which coexpressed HAI-1 ( P = 0.039). Conclusions : Advanced-stage ovarian tumors that express matriptase are more likely to do so in the absence of its inhibitor, HAI-1, indicating that an imbalance in the matriptase:HAI-1 ratio could be important in the development of advanced disease. Such an imbalance could promote the proteolytic activity of matriptase and, consequently, a more invasive phenotype.