The function of matrilysin and other matrix metalloproteinases in human prostate carcinoma
AdvisorNagle, Ray B.
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PublisherThe University of Arizona.
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AbstractMatrix metalloproteinases (MMPs) are involved in many normal and pathological processes that require remodeling of the extracellular matrix. In this dissertation, the distribution of MMPs in human prostate tissue was determined. Matrilysin localized to epithelial cells in prostate ducts surrounded by inflammatory cells, and was focally expressed in carcinoma and prostatic intraepithelial neoplasia, but not in normal glands. Gelatinase A was detected in both benign and malignant prostate tissue in similar amounts. MT-MMP1, an activator of progelatinase A, was present in 100% of the carcinomas, in 88% of the cases with PIN lesions, but only in 34% of the normal glands. Matrilysin converted gelatinase/TIMP-complexes and free gelatinase B into polypeptides with gelatinolytic activity. In contrast, matrilysin was unable to proteolytically cleave gelatinase A/TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Active matrilysin did not enhance the autocatalytic conversion of its own proform. Using indirect immunofluorescence microscopy, degradation of the fibronectin fibrils produced fibroblasts by matrilysin was demonstrated. Fibronectin fibrils represent a major component encountered by tumor cells during invasion. Removal of matrilysin resulted in regrowth of the fibrils, suggesting that matrilysin was not cytotoxic. Stable fragments derived from the gelatin-binding, the heparin-binding, and the cell attachment domains, respectively, of fibronectin, were identified. Their isolation may allow further studies on their influence on cell migration, attachment and signal transduction which are expected to be different from the effects of undegraded fibronectin. Effects of matrilysin on integrins were also investigated. Incubation of beta4, but not of alpha6 or beta1, with matrilysin, resulted in complete degradation in vitro. Thereby a specific fragment of 90 kD was generated, which was not observed with calpain or trypsin. Two putative cleavage sites for matrilysin at residues 107 (isoleucine) and 417 (leucine) located within the extracellular domain of the beta4 were identified by sequence comparisons with known substrates. Degradation of beta4 by matrilysin may partly explain the loss of beta4 integrin in prostate carcinoma. Taken together, the data presented here demonstrate effects of matrilysin on a variety of processes important in carcinogenesis.
Degree ProgramGraduate College