Page 141 - Molecular features of low-grade developmental brain tumours

DYSREGULATION OF MMP/TIMP IN SEGA: MODULATION BY MIR-320D IN VITRO
Figure 4. miR-320d is a predictive regulator of MMPs and is lower expressed in SEGA compared to control. a. Heatmap showing all under-expressed miRNAs in SEGA as compared to controls (adjusted p-value<0.05) predicted to target MMP2, MMP11, MMP14, MMP15 and/or MMP19 (based on miRWalk2). Green boxes indicate MMP19, MMP15, MMP14, MMP11 and/or MMP2 as predicted target of a specific miRNA. b. Relative expression of miR-320d in SEGA (n=12) as compared to control tissue (n=8). Data are expressed relative to the expression observed in control tissue. *p-value<0.05, **p-value<0.01, ***p-value<0.001, Mann-Whitney U test. c. In situ hybridization of miR-320d in periventricular white matter (wm) and gray matter (gm) control and SEGA tissue. Giant cells are indicated with arrows. Scale bar: 100 μm. d. The optical density per case for the in situ hybridization signal of miR-320d in periventricular control tissue (n=7/9) and SEGA (n=8). *p-value<0.05, ***p-value<0.001, Mann-Whitney U test.
MMP and TIMP expression in SEGA
Dysregulation of ECM organization in TSC cortical tubers and SEGA has been suggested by several transcriptome studies showing differential expression of genes related to the gene ontology term ECM organization, however the ECM has not been studied in detail in SEGA 24,26,27,29. In this study, we identified higher expression of MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP19, MMP25, TIMP1, TIMP2 and TIMP3 in SEGA as compared to controls. This suggests that the dysregulation of the MMP/TIMP proteolytic system is conserved across TSC pathology and might also affect migration during early brain development in TSC. In our previous study we showed higher expression of MMPs and TIMPs in non-SEGA material of TSC patients. Among others, higher expression of MMP2, MMP14, TIMP1, TIMP2 and TIMP3 was observed in cortical tubers of TSC patients as compared to control cortex. Moreover, increased protein expression of MMP2 and MMP14 was also observed in tubers of TSC patients and the expression of MMPs and TIMPs was associated with neuroinflammation and BBB dysfunction 28. This indicates that the overexpression of MMPs might not be SEGA-
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