Matrix metalloproteinase-26 (Matrilysin-2) expression is high in endometrial hyperplasia and decreases with loss of histological differentiation in endometrial cancer

Abstract

Objective. Matrix metalloproteinases (MMPs) are key players in the degradation of extracellular matrix and basement membranes, and are thus important in tumor invasion. Recently, MMP-26 (endometase), a novel matrilysin-type member of the MMP family, was cloned from an endometrial tumor. This study examines the expression of MMP-26 mRNA in hyperplastic, premalignant and malignant endometrial samples, and compares with normal endometrial tissue. Methods. Endometrial carcinoma samples (19) were histologically classified as well, intermediately and poorly differentiated. Samples with hyperplasia ( n = 15) were classified as simple, complex, or complex with atypia. Normal endometrial specimens ( n = 39) were classified according to an ideal 28-day menstrual cycle and subsequently grouped in the early, middle, and late parts of the cycle. All samples were analyzed using in situ hybridization and real time PCR. The probes used for in situ hybridization and real time PCR recognized non-overlapping sequences. MMP-26 protein was localized by immunohistochemistry. Results. MMP-26 mRNA was exclusively localized in the epithelial component of normal, hyperplastic, premalignant, as well as malignant samples. It was not found in the stroma of any tissue category. Quantifications with real time PCR as well as semi-quantifications of the in situ hybridization signal revealed maximal levels in normal tissue at midcycle and in endometrial hyperplasia both with and without atypia. The amount of MMP-26 mRNA decreased progressively with loss of histological differentiation in malignant samples. Immunostaining localized MMP-26 in epithelial glandular and luminal cells, in vessel walls, and in tumor cells. Since the pattern of MMP-26 expression mimicked that of ER-α, we searched the MMP-26 promoter region for a potential estrogen response element (ERE). A sequence at position −130 to −116 had high homology to the consensus sequence of an ERE. Based on these observations, we suggest that ER-α is involved in regulation of the MMP-26 gene. Conclusions. MMP-26 mRNA is selectively localized in the epithelial compartment of normal, hyperplastic, and malignant endometrial tissue. Expression is high in normal and hyperplastic endometria, but is downregulated in the late part of the cycle and in malignant tumors. The expression pattern of MMP-26 mRNA mimics that of ER-α, and the promoter region of the MMP-26 gene has a potential ERE.