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Gambari et al. J Cancer Metastasis Treat 2019;5:55 I http://dx.doi.org/10.20517/2394-4722.2019.18 Page 5 of 13

be insulin-like growth factors, fibroblast growth factor and their receptors [74,75] . Excellent review articles
describing current therapeutic approaches and novel trends in GBM management are available [69,76-82] .

In conclusion, since no curative treatment is available and the most used first-line drug, temozolomide
(TMZ), is only able to cause an increase of the life expectancy , new drugs are urgently needed for the
[69]
implementation of therapeutic protocols for anti-glioma treatments. Moreover, a high proportion of
gliomas become with time TMZ-resistant. Therefore, a deep interest does exist for combined treatments on
TMZ-resistant glioma cells in order to induce therapeutic relevant response, including, but not limited to,
apoptosis [81,82] .

MICRORNAS IN GLIOMAS: VARIABILITY AMONG THE PATIENTS HAMPERS THE IDENTIFICATION
OF POSSIBLE THERAPEUTIC TARGETS FOR PERSONALIZED TREATMENTS
Several studies available from the recent literature clearly support the involvement of microRNAs in
gliomas [83-93] , outlining a large number of miRNAs demonstrated to be dysregulated in these tumors. Of
course, these studies might indicate miRNA targets to be proposed for the development of protocols for
therapeutic intervention in glioma, including strategies useful to tackle the issue of drug resistance [94-96] .
Comprehensive analysis of microRNA expression profile in malignant glioma tissues has been reported by
Piwecka et al. , Banelli et al. , Ciafrè et al. . The analysis of microRNAs is also associated with tumor
[98]
[99]
[97]
onset and progression. For instance a miRNA signature was found associated with glioblastoma tumor
tissues. Up-regulated miRNAs were miR-221, miR-222, miR-22, miR-296-3p, miR-195, miR-155, miR-152,
miR-132, miR-146b-5p, miR-149, miR-129-3p, miR-34a, miR-671-5p, miR-10a. Down-regulated miRNAs were
let-7b, miR-767-5p, miR-505, miR-301b, miR-181a, miR-20a, miR-19a, miR-19b, miR-106a [97-99] . In any case, a
large consensus does exist on the fact that tumor tissues are highly heterogeneous with respect to molecular
and genetic features, supporting the concept that GBM represents a heterogeneous type of neoplasm when
the microRNA patterns are considered [100,101] .

However, due to global high-throughput profiling it is possible to select miRNAs that are at high risk of
being deregulated in the majority of patients. Thus, there is a considerable hope for utilizing miRNAs as
targets in prospects of glioma therapy. A partial list of validated miRNAs dysregulated in gliomas (with their
proposed mRNA targets) is reported in Supplementary Table S1.

Among the possible microRNA targets involved in glioma, miR-155-5p appears to be of relevant interest for
the following reasons: (1) miR-155-5p may play an important role in the transformation of normal neural stem
cell toward glioma stem cells ; (2) the elevated expression level of miR-155-5p promotes the proliferation
[102]
and invasion of glioblastoma cells through suppressing GABA receptors , FOXO3a and MXI1 ; (3) an
[105]
[104]
[103]
oligonucleotide targeting miR-155-5p was shown to sensitize glioma cells to taxol-induced apoptotic death ;
[106]
and (4) miR-155-5p overexpression is considered as a major molecular feature of glioblastoma, which can
discriminate this malignancy from a similar intracranial tumor, oligodendroglioma . Therefore, miR-
[107]
155-5p alone or together with other miRNAs is a predictive biomarker for glioma prognosis [107,108] . On the
other hand, glioma-targeting therapy based on miR-155-5p anti-oligonucleotides is believed to be efficient to
inhibit the progression of glioma .
[109]
However, several recent studies have pointed out that the translation of the analysis of the expression and
content of miR-155-5p and other miRNAs in gliomas into therapeutic strategy is hampered by the high
variability of microRNAs among patients [92,100,101] . For instance, in analyzing 31 tumor specimens against
paired normal tissue, Yan et al. found a significant upregulation of miR-155 in tumor tissues. This study
[92]
was based on the analysis of surgically dissected glioma specimens and their surrounding brain tissues. In
spite of the increased miR-155 expression, a large proportion of tumor samples exhibited a nearly normal