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

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.

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

“…A final pathological hallmark of TSC is the disruption of the blood-brain barrier (BBB) (108), with implications for a modulatory role of matrix metalloproteinases in BBB remodeling (62, [109][110][111][112][113]. In this context, chronic BBB dysfunction and epileptogenesis after status epilepticus (SE)-induced epilepsy could be reduced via treatment with rapamycin, pointing toward a more general role of mTOR-dependent BBB remodeling during epileptogenesis in epilepsy (34, 35, 114).…”

Experience using mTOR inhibitors for subependymal giant cell astrocytoma in tuberous sclerosis complex at a single facility

“…Neuroradiological follow-up was performed every 1-3 years concept of SEGA from emergent hydrocephalus treatment by a single department to prophylactic treatment by an interdisciplinary team appears warranted. Some differences between SEGA with and without iICP, such as variations in immunohistochemical features, genetic differences, and anaplastic features [50][51][52] or protein-producing functions [53,54], may relate to brain compliance or osmotic pressure. However, this study could not address this question.…”

“…Some differences between SEGA with and without iICP, such as variations in immunohistochemical features, genetic differences, and anaplastic features [ 50 – 52 ] or protein-producing functions [ 53 , 54 ], may relate to brain compliance or osmotic pressure. However, this study could not address this question.…”

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex

“…Furthermore, CD3 was not found differentially methylated between SEGA1 and SEGA2, suggesting an indirect effect of methylation on CD3 expression. The precise role of T-cells in SEGAs is still unknown, it could indicate a more responsive immune response to tumor cells but we also know that, neuroin ammation can increase the expression and activity of MMPs, which are increased in SEGAs and can play a role in tumorgenesis (Bongaarts et al 2020). The MAPK pathway has been shown to be an important pathway for SEGA growth and has been suggested as a novel target for therapy for patients with SEGA (Bongaarts et al 2019, Tyburczy et al 2010, Mi et al 2009).…”