miRNA Signaling
MicroRNAs (miRNA) physiological role is vital in controlling the cell
cycle, cell proliferation, differentiation, and apoptosis in normal
cells. Most tumor neoplasms such as, gastric, ovarian and uveal melanoma
cancers showed high levels of aberrant miRNAs expression. MiRNAs can act
as oncogenic miRNAs (onco-miRs) during tumor development and progression
based on their level of expression and their main targets are oncogenes
and tumor suppressor genes. As an example, in human glioblastoma (GBM)
cells, an endogenous miR-7 target the epidermal growth factor receptor
(EGFR) and independently inhibit this signalling pathway. High
expression of miR-7 in the GBM cell can activate the Akt signalling
pathway, thus enhance the invasiveness and viability of GBM cells
[22].
Specific lncRNAs may act as competing endogenous RNAs (ceRNAs) to
control miRNAs and subsequently affect the expression of their target
genes by absorbing or sponging the miRNAs in the cytoplasm
[23]. The ceRNAs are lncRNAs that
bind to miRNAs and prevent miRNAs from interacting with their target by
decoying or sponging [24]. For
example, ZFAS1 has been shown to sponge miRNAs, and influence
tumor growth in melanoma cancer by sponging miR-150-5p
[25], microRNA-200b-3p in gastric
cancer [26], miR-10a in clear cell
renal cell carcinoma [27], miR-329 in
bladder cancer [28], and miR-484 in
colorectal cancer [29]. In glioma,
studies show that ZFAS1 acts as a molecular sponge for miRNAs
such as miR-1271-5p[17], miR-150-5p
[30], and miR‐432‐5p
[31]. ZFAS1 is found primarily
in the cytoplasm of glioma cells, implying that it may play a role in
the ceRNA network, where ZFAS1 regulates target gene expression
via miRNA sponging [17].
Through three online bioinformatic databases prediction, starBase V3,
DIANA and miR code; miR-150-5p was
predicted as ZFAS1 ’s potential target, and following that, this
prediction was confirmed by luciferase reporter and RNA pull-down
analysis, where ZFAS1 was observed to act as a sponge for
miR-150-5p [30]. Furthermore, results
revealed that miR-150-5p’s
expression level in glioma was lower than in Normal Human Astrocytes
(NHA) [30]. Pearson’s correlation
coefficient analysis showed a negative correlation between miR-150-5p’s
expression and ZFAS1 ’s expression in glioma tissues. The glioma
tissues originated from patients who endured tumor resection (ten grade
IV, ten grade III, and seven grade II patients).
[30].
Moreover, the expression of an endoplasmic reticulum 4-transmembrane
protein, proteolipid protein 2 (PLP2), is found to be associated with
glioma cell proliferation, migration and invasion
[32].
PLP2 protein was discovered to be a functional target mRNA of miR-150-5p
[30]. The expression level of PLP2 in
glioma cell lines and tissues was higher than in normal brain tissue
(NBT), and this protein is implicated in glioma progression regulated by
miR-150-5p to inhibit tumor progression and decrease drug-resistance in
glioma cells. The same study revealed that ZFAS1 functions as a
miR-150-5p sponge to regulate PLP2 expression in promoting the
proliferation, migration and invasion while increasing resistance to TMZ
in glioma cells in vitro and in vivo , via immunodeficient
male nude mice [30]. In other
studies, miR-150-5p has been implicated in suppressing the progression
of several human cancers, such as melanoma cancer and epithelial ovarian
cancer (EOC) [33].
For instance, Liang et al.[25] found that miR-150-5p acts as a
tumor suppressor in melanoma cells by negatively regulating the
expression of Ras-related protein Rab9A (RAB9A ). The elevated
expression of ZFAS1 in melanoma tissues and cells promoted
melanogenesis, including proliferation, migration, and invasion, while
suppressing apoptosis via the ZFAS1 /miR-150-5p/RAB9A axis
[25]. Xia et al.[33] also reported that miR-150-5p is
involved in EOC, where this miRNA suppressed the malignancy and reduced
chemoresistance in EOC cells by targeting the expression of specificity
protein 1 (Sp1 ) . They found that ZFAS1 ’s expression was
overexpressed in EOC tissues and cell lines, and ZFAS1 directly
regulated miR-150-5p to promote the progression and chemoresistance in
EOC by regulating Sp1 [33].
ZFAS1 enhanced gliomagenesis through modulating the
miR-1271-5p/HK2 axis, where miR-1271-5p was suggested to beZFAS1 ’s potential target and Hexokinase 2 (HK2) was miR-1271-5p’s
target. ZFAS1 enhanced the expression level of HK2 in glioma
cells through sponging activity of miR-1271-5p, and subsequently
promoting the development of glioma. MiR-1271-5p was found to be
downregulated in glioma tissues, and a dual-luciferase reporter assay
confirmed the existence of an interaction between miR-1271-5p and ZFAS1.
It was reported that their interactions were negatively proportional
with each other [17]. Upregulation of
miR-1271-5p suppressed gliomagenesis by increasing apoptosis and
reducing glioma cell proliferation, migration, and invasion which is
consistent with earlier research findings
[34]. Additionally, the study
reported that ZFAS1 and HK2 protein expression in glioma tissues
exhibited a positive correlation, whereas HK2 and miR-1271-5p protein
expression exhibited an inverse correlation
[17]. HK2 was found to be the key
enzyme that contributes significantly to the Warburg effect. Warburg
effect is a term to indicate cancer cells’ preference to metabolise
glucose anaerobically. High expression of HK2 can lead to chemo- or
radiation resistance of glioma cells via the aberrant of the apoptosis
pathway [35].
Apart from miR-150-5p and miR-1271-5p, ZFAS1 can also sponge
miR-432-5p. A study has shown that ZFAS1 and miR‐432‐5p had a
significant negative association where miR‐432‐5p was a direct target ofZFAS1 to modulate glioma cells viability and cisplatin resistance
[31]. miR‐432‐5p expression was found
to be downregulated in glioma tissues and cell lines, while
overexpression of this miRNA lowered glioma cell viability and enhanced
cisplatin-induced glioma cell death
[36]. In breast cancer tissues,
miR‐432‐5p expression level was found to be downregulated as compared to
neighbouring healthy tissues [37].