Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro

Anika Bongaarts*, Jody M de Jong, Diede W M Broekaart, Jackelien van Scheppingen, Jasper J Anink, Caroline Mijnsbergen, Floor E Jansen, Wim G M Spliet, Wilfred F A den Dunnen, Victoria E Gruber, Theresa Scholl, Johannes A Hainfellner, Martha Feucht, Julita Borkowska, Katarzyna Kotulska, Sergiusz Jozwiak, Wieslawa Grajkowska, Anna Maria Buccoliero, Chiara Caporalini, Flavio GiordanoLorenzo Genitori, Brendon P Scicluna, Antoinette Y N Schouten-van Meeteren, Erwin A van Vliet, Angelika Mühlebner, James D Mills, Eleonora Aronica

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    15 Citations (Scopus)
    166 Downloads (Pure)

    Abstract

    Tuberous sclerosis complex (TSC), a rare genetic disorder caused by a mutation in the TSC1 or TSC2 gene, is characterized by the growth of hamartomas in several organs. This includes the growth of low-grade brain tumors, known as subependymal giant cell astrocytomas (SEGA). Previous studies have shown differential expression of genes related to the extracellular matrix in SEGA. Matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) are responsible for remodeling the extracellular matrix and are associated with tumorigenesis. This study aimed to investigate the MMP/TIMP proteolytic system in SEGA and the regulation of MMPs by microRNAs, which are important post-transcriptional regulators of gene expression. We investigated the expression of MMPs and TIMPs using previously produced RNA-Sequencing data, real-time quantitative PCR and immunohistochemistry in TSC-SEGA samples and controls. We found altered expression of several MMPs and TIMPs in SEGA compared to controls. We identified the lowly expressed miR-320d in SEGA as a potential regulator of MMPs, which can decrease MMP2 expression in human fetal astrocyte cultures. This study provides evidence of a dysregulated MMP/TIMP proteolytic system in SEGA of which MMP2 could be rescued by microRNA-320d. Therefore, further elucidating microRNA-mediated MMP regulation may provide insights into SEGA pathogenesis and identify novel therapeutic targets.

    Original languageEnglish
    Article numbernlaa040
    Pages (from-to)777-790
    Number of pages14
    JournalJournal of neuropathology and experimental neurology
    Volume79
    Issue number7
    DOIs
    Publication statusPublished - Jul-2020

    Keywords

    • Extracellular matrix
    • Matrix metalloproteinases
    • MicroRNA
    • Subependymal giant cell astrocytoma (SEGA)
    • Tuberous sclerosis complex
    • CENTRAL-NERVOUS-SYSTEM
    • MATRIX METALLOPROTEINASES
    • CORTICAL TUBERS
    • GENE-EXPRESSION
    • TUMORS
    • BRAIN
    • ACTIVATION
    • MIGRATION
    • TSC1
    • MATRIX-METALLOPROTEINASE-9

    Fingerprint

    Dive into the research topics of 'Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro'. Together they form a unique fingerprint.

    Cite this