Page 182 - Molecular features of low-grade developmental brain tumours

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CHAPTER 7
In gliomas the expression of MMPs correlate with WHO classification and overall
survival 77-80. However, SEGAs are slow-growing, WHO grade I tumours and are generally not
associated with poor survival. A previous study found increased expression of TIMP1 and
TIMP2 in grade I brain tumours compared to grade II or III tumours 81. The higher expression
of TIMPs in SEGA may act as a compensatory mechanism for higher MMP expression, which
could explain why the higher expression of MMPs does not lead to metastases and excessive
growth in SEGAs. Interestingly, RT-qPCR analysis revealed higher expression of MMP19 in
recurrent/regrown SEGAs as compared to nonrecurrent/regrown SEGA. Previous studies
found a correlation between MMP19 expression and tumour malignance/invasion, suggesting
MMP19 could be a potential biomarker for recurrence/regrowth 78,80,82. However, our sample
size of recurrent/regrown SEGAs was small and this effect was not found in the RNA-Seq
data. Therefore, further investigation on the role of specific MMPs in SEGA development
and growth is needed. Since MMPs are known to play a role in tumourgenesis and epilepsy
the MMP/TIMP proteolytic system might also be an interesting target for investigation and
future therapies for LEATs. Several MMP inhibitors exist that can regulate MMP overactivity.
However, the currently available MMP inhibitors can have a variety of side effects indicating
the complexity of MMP regulation 83. Alternatively, microRNAs (miRNAs) have been shown to
participate in MMP regulation at the post-transcriptional level in TSC tuber-derived astroglial
cultures and glioma cell lines and could therefore also be of interest in targeting MMPs in SEGA 71,84,85.
microRNAs in low grade gliomas
So far, research on small non-coding RNAs in SEGA has been limited to miRNA expression using microarray analysis 86. In chapter 4 we investigated the small non-coding RNA profile of SEGAs and found that miRNAs, snRNAs, snoRNAs and vtRNAs were amongst the differentially expressed small RNAs. Additionally, a high number of unannotated small transcripts were identified and although they still need validation as well as functional characterization, they could potentially harbour novel small RNAs. The largest group of differentially expressed small RNAs in SEGA compared to control were miRNAs. Since miRNAs can regulated gene expression a bioinformatics approach was used to identify miRNAs that could potentially modulate some of the enriched pathways found in chapters 3 & 4. In chapter 4 we identified miRNA-20a-5p as a potential regulator of several LAMTOR genes and in chapter 5 we identified miRNA-320d as a potential regulator of MMP genes. Interestingly, miR-20a-5p is also predicted to target MMP2, MMP11 and MMP19. Other studies have shown the potential of miR-20a-5p in modulating MMP/TIMP expression in in vitro models of various type of cancers suggesting that miR-20a-5p could also modulate the MMP/TIMP proteolytic system 87-89. However, we did not further investigate the role miR-20a-5p on MMP/TIMP expression and ECM in SEGAs. Previous research identified miR-320d as a regulator of MMP2, decreasing MMP2 protein expression in glioma cell lines, inducing cell apoptosis and suppressing cell growth and migration 85. In accordance with this study, we found that miR-320d can target MMP2 in human fetal astrocytes, but did not affect the expression of MMP11, MMP14, MMP15,