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Page 6 of 14 Santoni et al. J Cancer Metastasis Treat 2020;6:22 I http://dx.doi.org/10.20517/2394-4722.2020.49
[36]
strongly reduces glioma cell viability in both in vitro and in vivo experimental models . This suggests
miR-10b gene editing to be a promising therapeutic approach for permanent elimination of essential
regulators of tumor survival.

In addition, the miR-17-92 locus has been found to be amplified in GBM specimens. Inhibition of miR-17-92
activities enhances apoptosis and reduces cell proliferation of GBM spheroids. miR-17-92 inhibition has
also been associated with increased expression of CTGF, a direct target of miR-17-92 in GBM spheroids, as
[37]
well as CDKN1A, E2F1, PTEN .

Several target of miRs are represented by members of the TGF/SMAD pathways. In GBM tissues
overexpressing miR-92b, the expression of SMAD3 was found to be reduced when compared with that of
normal brain tissues. miR-92b directly affects SMAD3 expression by targeting the 3’-untranslated region.
Cip1
Silencing miR-92b inhibits GBM viability through upregulation of the TGF/SMAD3/p21 signaling
pathway. Furthermore, in vivo treatment with miR-92b inhibitors was shown to reduce tumor growth,
demonstrating the ability of miR-92b to act as an oncogene by promoting GBM cell proliferation. Therefore,
miR-92b may be a future potential target for the development of miR-based therapies . miR-193b has also
[38]
been shown to be upregulated in glioma patients, while its overexpression has been associated with poor
prognosis. Downregulation of miR-193b correlates with decreased cell growth. SMAD3 is a direct target of
miR-193b, and downregulation of SMAD3 attenuates miR-193b suppression of glioma proliferation. Thus,
[39]
miR-193b regulates cell growth through the TGF-β pathway by modulating SMAD3 .
Upregulation of miR-93 has also been demonstrated to be associated with advanced malignancy as it
promotes the proliferation, migration and invasion of glioma cells. miR-93 regulates the cell cycle by
controlling the p21 , p27 KIP1 , p53 and cyclin D1 expression. Since p21 is a direct target of miR-93,
Cip1
Cip1
p21 Cip1 knockout attenuates the suppressive effects of miR-93 on cell cycle progression and colony
formation. In addition, the chemosensitization of GBM cells to temozolomide is markedly increased when
[40]
miR-93 is inhibited . Overexpression of miR-149 in gliomas augments pro-survival activity, inhibits
apoptosis and induces xenografted tumor growth in vivo. Given that caspase-2 is a functional target of
miR-149, its expression is inversely associated with miR-149 in vitro. miR-149 promotes cell survival in U87
and A172 glioma cell lines and targets caspase-2, through p53 and p21 inactivation .
[41]
Cip1
Several miRs have be found to be down-regulated in glioma patients, thus functioning as tumor suppressor
genes (e.g., miR-34a, -128, -184, -223 -329 and -656). miR-34a maps to chromosome 1p36.23, a region often
deleted in GBM. For this reason, the expression of miR-34a is lower in GBM samples as compared with
that of normal brain tissue. In glioma patients, an miR-34a deletion is accompanied by the amplification
of epidermal growth factor receptor (EGFR). Notably, mean survival time is shorter in GBM patients with
[42]
EGFR amplification and miR-34a deletion . Moreover, enforced expression of miR-34a in GBM cells
decreases migration and levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinases, while
increasing the expression of cyclin kinase inhibitor proteins such as p21 or p27 KIP1 . In in vivo xenograft
mouse model, the injection of U251 cells overexpressing miR-34a induced the development of smaller
tumors compared with tumors derived from wild-type U251 cells. Since miR-34a targets Yin Yang-1, a
transcription factor that stimulates the expression of EGFR, the expression of EGFR is reduced in cells
overexpressing miR-34a. miR-34a act as a tumor suppressor by inhibiting the growth of GBM cells in vitro
and in vivo .
[42]
miR-128 expression reduced glioma cell proliferation in vitro and in vivo in a glioma xenograft growth
model. It reduced Bmi-1 oncogene expression, by direct regulation of the Bmi-1 mRNA 3’-untranslated
region, through a miR-128 binding site. Relative to normal brain tissues, Bmi-1 is upregulated and miR-128
is down-regulated in glioma samples. Bmi-1 induces the silencing of several genes through epigenetic