title: Reduced activity of CD13/aminopeptidase N (APN) in aggressive meningiomas is associated with increased levels of SPARC.
abstract: Meningiomas are the second most common brain tumors in adults, and meningiomas exhibit a tendency to invade adjacent structures. Compared with high-grade gliomas, little is known about the molecular changes that potentially underlie the invasive behavior of meningiomas. In this study, we examined the expression and function of the membrane alanyl-aminopeptidase [mAAP, aminopeptidase N (APN), CD13, EC3.4.11.2] zinc-dependent ectopeptidase in meningiomas and meningioma cell lines, based on its prior association with tumor invasion in colorectal and renal carcinomas. We found a significant reduction of APNmRNA and protein expression, as well as enzymatic activity, in high-grade meningiomas. While meningioma tumor cell proliferation was not affected by either pharmacologic APN inhibition or siRNA-mediated APN silencing, APN pharmacologic and siRNA knockdown significantly reduced meningioma cell invasion in vitro. Next, we employed pathway-specific cDNA microarray analyses to identify extracellular matrix and adhesion molecules regulated by APN, and found that APN-siRNA knockdown substantially increased the expression of secreted protein, acidic and rich in cysteine (SPARC)/osteonectin. Finally, we demonstrated that SPARC, which has been previously associated with meningioma invasiveness, was increased in aggressive meningiomas. Collectively, these results suggest that APN expression and enzymatic function is reduced in aggressive meningiomas, and that alterations in the balance between APN and SPARC might favor meningioma invasion.
authors.affiliation: Department of Neuropathology, Friedrich Schiller University, Jena, Germany. christian.mawrin@med.ovgu.de
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.forename: Carmen
authors.initials: C
authors.lastname: Wolke
authors.forename: Daniela
authors.initials: D
authors.lastname: Haase
authors.forename: Sabine
authors.initials: S
authors.lastname: Krüger
authors.forename: Raimund
authors.initials: R
authors.lastname: Firsching
authors.forename: Gerburg
authors.initials: G
authors.lastname: Keilhoff
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Anita
authors.initials: A
authors.lastname: Lal
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
mesh_terms: D000328:Adult; D015153:Blotting, Western; D018826:CD13 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008579:Meningioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D015676:Osteonectin / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015676:Osteonectin; D034741:RNA, Small Interfering; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D018826:CD13 Antigens