TY - JOUR
T1 - 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
AU - Bongaarts, Anika
AU - de Jong, Jody M.
AU - Broekaart, Diede W. M.
AU - van Scheppingen, Jackelien
AU - Anink, Jasper J.
AU - Mijnsbergen, Caroline
AU - Jansen, Floor E.
AU - Spliet, Wim G. M.
AU - den Dunnen, Wilfred F. A.
AU - Gruber, Victoria E.
AU - Scholl, Theresa
AU - Hainfellner, Johannes A.
AU - Feucht, Martha
AU - Borkowska, Julita
AU - Kotulska, Katarzyna
AU - Jozwiak, Sergiusz
AU - Grajkowska, Wieslawa
AU - Buccoliero, Anna Maria
AU - Caporalini, Chiara
AU - Giordano, Flavio
AU - Genitori, Lorenzo
AU - Scicluna, Brendon P.
AU - Schouten-van Meeteren, Antoinette Y. N.
AU - van Vliet, Erwin A.
AU - Mühlebner, Angelika
AU - Mills, James D.
AU - Aronica, Eleonora
N1 - With supplementary file
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - Extracellular matrix
KW - Matrix metalloproteinases
KW - MicroRNA
KW - Subependymal giant cell astrocytoma (SEGA)
KW - Tuberous sclerosis complex
UR - http://www.scopus.com/inward/record.url?scp=85086792886&partnerID=8YFLogxK
UR - https://pure.uva.nl/ws/files/48938229/nlaa040_supplementary_data.png
U2 - https://doi.org/10.1093/jnen/nlaa040
DO - https://doi.org/10.1093/jnen/nlaa040
M3 - Article
C2 - 32472129
SN - 0022-3069
VL - 79
SP - 777
EP - 790
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 7
ER -
