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

被引：14

作者：

Bongaarts, Anika ^{[1
]}

de Jong, Jody M. ^{[1
]}

Broekaart, Diede W. M. ^{[1
]}

van Scheppingen, Jackelien ^{[1
]}

Anink, Jasper J. ^{[1
]}

Mijnsbergen, Caroline ^{[1
]}

Jansen, Floor E. ^{[2
]}

Spliet, Wim G. M. ^{[3
]}

den Dunnen, Wilfred F. A. ^{[4
]}

Gruber, Victoria E. ^{[5
]}

Scholl, Theresa ^{[5
]}

Hainfellner, Johannes A. ^{[6
]}

Feucht, Martha ^{[5
]}

Borkowska, Julita ^{[7
]}

Kotulska, Katarzyna ^{[7
]}

Jozwiak, Sergiusz ^{[7
,8
]}

Grajkowska, Wieslawa ^{[9
]}

Buccoliero, Anna Maria ^{[10
]}

Caporalini, Chiara ^{[10
]}

Giordano, Flavio ^{[11
]}

Genitori, Lorenzo ^{[11
]}

Scicluna, Brendon P. ^{[12
]}

Schouten-van Meeteren, Antoinette Y. N. ^{[13
,14
]}

Van Vliet, Erwin A. ^{[1
,15
]}

Muhlebner, Angelika ^{[1
]}

Mills, James D. ^{[1
]}

Aronica, Eleonora ^{[1
,16
]}

机构：

[1] Univ Amsterdam, Dept Neuro Pathol, Amsterdam Neurosci, Amsterdam UMC, Amsterdam, Netherlands

[2] Univ Med Ctr, Dept Pedit Neurol, Utrecht Brain Ctr, Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands

[5] Med Univ Vienna, Dept Pediat, Vienna, Austria

[6] Med Univ Vienna, Inst Neurol, Vienna, Austria

[7] Childrens Mem Hlth Inst, Dept Neurol & Epileptol, Warsaw, Poland

[8] Med Univ Warsaw, Dept Child Neurol, Warsaw, Poland

[9] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland

[10] Anna Meyer Childrens Hosp, Pathol Unit, Florence, Italy

[11] Anna Meyer Childrens Hosp, Dept Neurosurg, Florence, Italy

[12] Univ Amsterdam, Ctr Expt & Mol Med, Amsterdam UMC, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands

[13] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[14] Emma Childrens Hosp, Amsterdam UMC, Dept Pediat Oncol, Amsterdam, Netherlands

[15] Univ Amsterdam, Ctr Neurosci, Swammerdam Inst Life Sci, Amsterdam, Netherlands

[16] Stichting Epilepsie Instellingen Nederland SEIN, Heemstede, Netherlands

来源：

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY | 2020年 / 79卷 / 07期

基金：

奥地利科学基金会; 欧盟地平线“2020”;

关键词：

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;

D O I：

10.1093/jnen/nlaa040

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：777 / 790

页数：14

共 79 条

[1] Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature [J].