Abstract
Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene.Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities.Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.
Highlights
Glioblastoma (GBM) is the most common and fatal malignant primary brain tumor in adults
In order to identify miRNAs relevant for glioblastoma stem-like cells (GSCs) tumorigenesis, we analyzed by real time PCR a panel of 48 miRNAs previously described as differentially expressed between normal and tumor tissue in GBM patients [1621], in a collection of GSC lines [22] compared with normal neural stem cell lines isolated from human adult olfactory bulb and foetal brain [23]
Decreased miR-135b and miR-21 levels were observed in both xenograft models as compared to cultured tumor generating GSCs, indicating that microenvironment may contribute to miRNA regulation
Summary
Glioblastoma (GBM) is the most common and fatal malignant primary brain tumor in adults. The molecular characterization of GBM is unveiling new potential therapeutic strategies based on targeting specific components of oncogenic pathways, e.g., by delivering a therapeutic gene or microRNA (miRNA) [3,4,5,6]. Several miRNAs are differentially expressed in a variety of malignancies compared to corresponding healthy tissues. Some of these miRNAs have been shown to play important roles in cancer cell proliferation, aggressiveness and metastasis. MiRNAs might hold a great potential in the future treatment of GBM tumor. This prompted us to identify and to study miRNAs deregulated in GSCs isolated from GBM patients
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