Metalloproteinases ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas

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Invasion of tumor cells critically depends on cell-cell or cell-extracellular matrix interactions. Enzymes capable of modulating these interactions belong to the proteinase families of ADAM (a disintegrin and metalloprotease) and MMP (matrix metalloprotease) proteins. Our objective is to examine their expression levels and evaluate the relationship between expression levels and cavernous sinus invasion in pituitary adenomas. Tissue samples from 35 patients with pituitary adenomas were analyzed. Quantitative real-time polymerase chain reaction (qPCR) was employed to assess mRNA expression levels for ADAM and MMP genes. Protein levels were examined using immunohistochemistry and Western Blot. Correlation analyses between expression levels and clinical parameters were performed. By silencing ADAM12 and MMP-14 with siRNA in a mouse pituitary adenoma cell line (TtT/GF), their cellular effects were investigated. In our study, nine women and 26 men were included, with a mean age of 53.1 years (range 15–84 years) at the time of surgery. There were 19 cases with cavernous sinus invasion. The proteins ADAM12 and MMP-14 were significantly up-regulated in invasive adenomas compared to noninvasive adenomas. Both human isoforms of ADAM12 (ADAM12L and ADAM12s) were involved in tumor invasion; moreover, ADAM12L was found to correlate positively with Ki-67 proliferation index in pituitary adenomas. In TtT/GF pituitary adenoma cells, silencing of ADAM12 and MMP-14 significantly inhibited cell invasion and migration, respectively, whereas only silencing of ADAM12 suppressed cell proliferation. We conclude that ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas, which qualifies these proteins in diagnosis and therapy.

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Around a third of pituitary adenomas invade surrounding tissues. The mechanisms underlying the invasiveness and malignancy of pituitary adenomas, however, remain poorly understood. This study evaluated the relationship between the expression levels of two protein families associated with tumor invasion—A Disintegrin And Metalloproteinase (ADAM) and Matrix Metalloproteinases (MMP)—and cavernous sinus invasion in pituitary adenomas. The authors measured ADAMs and MMPs expression in human pituitary adenomas and performed gene silencing experiments in rodent pituitary adenoma cells. ADAM12 and MMP-14 exhibited a potential role in invasion and proliferation of pituitary adenomas, which makes them potential targets for diagnosis and therapy.

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