Abstract
Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The miRNA profiling revealed 30 miRNAs to be differentially expressed. In total 13 miRNAs were upregulated and 17 downregulated in migrating cells compared to corresponding spheroids. The three most deregulated miRNAs, miR-1227 (up-regulated), miR-32 (down-regulated) and miR-222 (down-regulated), were experimentally overexpressed. A non-significantly increased migration rate was observed after miR-1227 overexpression. A significantly reduced migration rate was observed after miR-32 and miR-222 overexpression. In conclusion a shift in microRNA profile upon glioma cell migration was identified using an assay avoiding serum-induced migration. Both the miRNA profiling and the functional validation suggested that miR-1227 may be associated with increased migration and miR-32 and miR-222 with decreased migration. These miRNAs may represent potential novel targets in migrating glioma cells.
Highlights
Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults
The original U251 cell line was capable of migration reaching a distance and speed similar to the five GBM spheroid cultures earlier characterized [17]
A maximum migration speed was reached after 18 h for all cultures except the T87 GBM spheroid culture, which reached a maximum after 48 h (Fig. 2b)
Summary
Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Despite multimodal treatment options including surgery, radiation and chemotherapy, patients with GBM have an overall poor outcome with a mean survival of 14.6 months [1] and a 5-year survival rate of 9.8% [2]. Gliomas are highly invasive and migrate into the normal brain parenchyma along vessels and white matter fiber-tracts [3]. Migrating tumor cells will always be left behind despite surgery. The underlying phenotype characterizing highly aggressive migrating tumor cells causing short survival and treatment failure is not yet fully understood. As cancer stem cells (CSCs) have been shown to be both radio- and
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