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Santoni et al. J Cancer Metastasis Treat 2020;6:22 I http://dx.doi.org/10.20517/2394-4722.2020.49 Page 7 of 14

chromatin modifications. It is responsible for decreasing histone methylation [H3K27me(3)] and Akt
Cip1
phosphorylation, while upregulating p21 levels. Bmi-1 also promotes self-renewal of stem cells, while
[43]
miR-128 [by down-regulating Bmi-1 levels] inhibits self-renewal of glioma . miR-184 levels are reduced
in aggressive human tumor cells. Thus, a potential therapeutic strategy which targets miR-184 may prove
useful in reducing cancer aggressiveness. miR-184 inhibits the proliferation and invasion of the U87MG
Cip1
cell line. It arrests the cell cycle and prevents adhesion by upregulating the expression of p53 and p21 ,
increasing caspase-3/8 activity, suppressing SND1, MMP-2/9, CD44 expression, and the activity of the
[44]
AKT/NF-κB pathway . Another miR involved in glioma development is miR-223. It represses nuclear
factor I-A (NFIA) expression, a key regulator of gliogenesis. miR-223 and NFIA expression negatively
correlate in human GBM tumors. The miR-223/NFIA axis suppresses tumorigenesis in human glioma cells.
Cip1
The NFIA factor directly represses p21 , and is required for tumorigenesis in a mouse neural stem cell
[45]
model of glioma .
miR-329, which is located on 14q32.31, is down-regulated in glioma and it is able to target E2F1. Its
overexpression blocks G1/S transition in LN18 and T98G cell lines and suppresses cell proliferation as
well as colony formation. It also decreases the phosphorylation of Akt and cyclin D1, inducing p21
Cip1
[46]
upregulation and suppression of cell growth through the inhibition of the E2F1-mediated Akt pathway .
miR-656 was found to be downregulated in glioma. In human glioma tissues, expression of BMPR1A [a
miR-656 target] is negatively correlated with miR-656 levels. miR-656 suppresses glioma cell proliferation,
[47]
neurosphere formation, migration and invasion with or without exogenous BMP-2 . Knockdown of
BMPR1A diminished the antiproliferative effect of miR-656 in vitro. Moreover, the canonical BMP/SMAD
pathways were shown to be inhibited by miR-656 overexpression. Several molecules, including cyclin B,
KIP1
Cip1
cyclin D1, matrix metalloproteinase-9, p21 and p27 are involved in miR-656 functions within glioma
cells. Ectopic expression of miR-656 reduced tumor size and prolonged the survival of mice, regardless of
whether treatment with BMP-2 was administered .
[47]
Some miRs, even if down-regulated in gliomas, function as tumor promoters. For example, an important
role has been described for miR-454, which is down-regulated in GBM primary tumors and cell lines.
Overexpression of miR-454 in GBM cells resulted in the arrest at the G0/G1 phase, resulting in the
inhibition of cell proliferation. 3-phosphoinositide-dependent protein kinase-1 (PDK1), one of miR-454
targets, was found to increase miR-454 levels, decrease PDK1 expression, down-regulate Cyclin D1 and
upregulate p-Rb and p21 Cip1[48] .

In addition, arsenic resistance protein 2 (Ars2), a component of the nuclear RNA cap-binding complex,
that is involved in miR biogenesis, proliferation and tumorigenicity, was found to be overexpressed
[49]
[49]
in glioma cell lines . It is also associated with poorer overall survival in GBM patients . In fact, not
only several miRs have been found to be associated with pathological grade, tumor development and
stemness in glioma [50,51] , but also it has been demonstrated that overexpression of Ars2 stimulates glioma
cell proliferation and colony formation and colony formation. Knockdown of Ars2 reduces miR-6798-3p
Cip1
expression, causing p53 and p21 upregulation which leads to apoptosis. By using an orthotopic GBM
xenograft model, knockdown of Ars2 was found to reduce tumor growth and to extend the survival time of
[49]
tumor-bearing mice .

ROLE OF LONG NON-CODING AND LONG INTERGENIC NON-CODING RNAS IN GLIOMA AND
GLIOMA STEM CELLS
Long noncoding RNAs (LncRNAs) represent a class of long transcribed noncoding RNAs (ncRNA)
molecules, which are longer than 200 nucleotides. They do not code for proteins and are involved in tumor