Bocheva Georgeta, Rattenholl Anke, Kempkes Cordula, Goerge Tobias, Lin Chen-Yong, D'Andrea Michael R, Ständer Sonja, Steinhoff Martin
University of Münster, Münster, Germany.
J Invest Dermatol. 2009 Jul;129(7):1816-23. doi: 10.1038/jid.2008.449. Epub 2009 Feb 26.
Matriptase (membrane-type serine proteinase) was reported to play a role in nonmelanoma skin cancer progression. Moreover, it was shown to stimulate proteinase-activated receptor-2 (PAR(2)) in vitro. Hepatocyte growth factor activator inhibitor-1 (HAI-1), the matriptase inhibitor, is an important regulator of enzyme activity. Therefore, the aim of this study was to elucidate the putative role of matriptase, HAI-1, and PAR(2) in normal human skin, as well as in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). In normal human epidermis, PAR(2) colocalized with matriptase and HAI-1. Immunoreactivity of all proteins was found to be diminished in BCCs. Likewise, PAR(2) immunoreactivity was significantly decreased, whereas matriptase immunoreactivity was enhanced with SCC progression. We could also show that matriptase was complexed to HAI-1 in normal human skin, whereas in SCCs, the enzyme was present in an unassociated form. Both a specific peptide agonist for PAR(2) and the proteinase domain of matriptase were able to induce intracellular calcium mobilization and inhibition of proliferation in cultured HaCaT keratinocytes. In conclusion, our results suggest that PAR(2) is a substrate for matriptase in human skin in vivo. Deregulation of these proteins delineates SCC progression.
据报道，膜型丝氨酸蛋白酶（Matriptase）在非黑色素瘤皮肤癌进展中发挥作用。此外，在体外实验中发现它能刺激蛋白酶激活受体-2（PAR(2)）。肝细胞生长因子激活剂抑制剂-1（HAI-1）作为Matriptase的抑制剂，是酶活性的重要调节因子。因此，本研究的目的是阐明Matriptase、HAI-1和PAR(2)在正常人类皮肤以及基底细胞癌（BCC）和鳞状细胞癌（SCC）中的假定作用。在正常人类表皮中，PAR(2)与Matriptase和HAI-1共定位。在BCC中发现所有蛋白质的免疫反应性均降低。同样，随着SCC进展，PAR(2)免疫反应性显著降低，而Matriptase免疫反应性增强。我们还发现，在正常人类皮肤中Matriptase与HAI-1形成复合物，而在SCC中，该酶以未结合的形式存在。PAR(2)的特异性肽激动剂和Matriptase的蛋白酶结构域均能够诱导培养的HaCaT角质形成细胞内的钙动员并抑制其增殖。总之，我们的结果表明，PAR(2)在体内是人类皮肤中Matriptase的底物。这些蛋白质的失调描绘了SCC的进展情况。
