EXPRESSION AND TISSUE LOCALIZATION OF MEMBRANE-TYPES 1, 2, AND 3 MATRIX METALLOPROTEINASES IN HUMAN UROTHELIAL CARCINOMAS

Abstract

Three different membrane-type matrix metalloproteinases (MT1, 2, 3-MMP) which can activate proMMP-2 (progelatinase A) are thought to have an important role in various human carcinoma invasions and metastases. We examined the mRNA expression of MT-MMPs and the tissue immunolocalization of MT1-MMP in human urothelial carcinomas. mRNA was extracted from 27 clinical urothelial carcinomas and 10 normal urothelial mucosa tissues remote from the tumor. RT-PCR using specific primers was performed, and PCR products were hybridized to³² P-labeled internal probes and analyzed by a bioimage analyzer. Immunolocalization was studied using a monoclonal antibody against MT1-MMP (114-6G6). MT1-MMP and MT2-MMP mRNA expressions in urothelial carcinomas were significantly higher than those in the normal mucosa. In contrast, MT3-MMP mRNA was little expressed in both tissues, and the amount of MT3-MMP mRNA appeared to be much lower than MT1-MMP and MT2-MMP in the tissue samples. In terms of the tumor multiplicity, MT1-MMP and MT2-MMP mRNA expressions in the group of multiple tumors were significantly higher than those in the solitary tumor group. The carcinoma cells were immunostained for MT1-MMP predominantly in invasive and superficial carcinoma cells. The immunoreactivity was more intense in the invasive type than in the superficial type. It is suggested that MT1-MMP and MT2-MMP play an important role in the development of human urothelial carcinomas and reflect some aspects of the pathogenesis of multifocal occurrence. In spite of the possible contribution to the invasive and metastatic phenotype, MT1-MMP mRNA and its product are thought to be expressed already in the clinical superficial stage in some cases of this tumor type.