Introduction
The GLOBOCAN cancer incidence and mortality database estimated that
308,102 new cases of brain cancer and 251,329 deaths from brain cancer
occurred in 185 countries in 2020 [1].
Gliomas, which originate in the brain or spinal cord’s glial cells,
account for more than 80% of all malignant brain tumours and are the
leading cause of brain tumour death worldwide
[2]. According to the 2007 World
Health Organization (WHO) classification of central nervous system (CNS)
tumours, gliomas were classified based on their cell type; astrocytoma,
oligodendroglioma, ependymoma, or mixed tumour (e.g., oligoastrocytoma).
They are divided into four grades based on the degree of malignancy from
least (low-grade; I and II) to most aggressive (high-grade; III and IV)
[3]. Despite advancements in the
treatment of malignant glioma through surgical, radiotherapy,
chemotherapy, and a combination of multiple therapies, the prognosis
remains poor due to tumour invasion, metastasis, and chemoresistance,
with the majority of grade IV glioblastoma patients living for less than
two years [4]. Thus, finding possible
diagnostic and prognostic molecular markers to aid the development
of glioma treatments is crucial. In addition, the dysregulation of
lncRNAs can be a potential biomarker in glioma diagnosis, prognosis, and
target therapy[5].
There are several reliable biomarkers for glioma, available such as;
1p/19q codeletion, MGMT promoter hypermethylation, IDH mutations,
circulating tumor DNA (ctDNA), and circulating tumor RNA (ctRNA) include
mRNAs, long non-coding RNAs (lncRNAs), and small non-coding RNAs
(snRNAs) [6]. lncRNAs are transcripts
with more than 200 nucleotides that lack functional open reading frames
[7]. Recently, studies reported that
lncRNA plays an important role in modulating comprehensive cellular
process by regulating transcriptional gene expression, and
post-transcriptional as well as epigenetic modification
[8]. In addition, lncRNA is a molecule
that has recently been shown to play an important role in cancer
signalling. They exert their influence through a variety of different
mechanisms of action. The molecular decoy mechanism, also known as
competitive endogenous RNA, is frequently described. Using this
mechanism, lncRNAs can bind molecules such as microRNA (miRNA) and
prevent them from mediating their effect on downstream gene signalling
[5]. Besides, the loss of lncRNA
expression could potentially alter the expression of many genes and
promote tumorigenesis. Reported lncRNAs associated with glioblastoma areMALAT1, H19 [9] HOTAIR ,
and GAS5 [6].
In general, these lncRNAs could regulate important oncogenic and tumour
suppressive pathways and significantly affect glioma development by
metastasis, tumorigenesis, chemoresistance, radioresistance, apoptosis,
and angiogenesis through various pathways, such as, PI3K/Akt,
Wnt/β-catenin or ERK/MAPK pathways. For example, MALAT1 suppress
apoptosis and increase the cell proliferation and viability of
glioblastoma (GBM) stem cell. Baspinar et al.[10] reported that downregulation ofMALAT1 decrease the stemness nestin and sex-determining region
(SRY) Y-box 2 (SOX2) markers in SHG139S GBM cells and induced cell
proliferation through ERK/MAPK pathway. MALAT1 excision (gene
silencing) inhibited glioma stem cell proliferation by increasing
miR-129 expression, which lowered glioma stem cell viability and growth
by inhibiting SOX2 expression
[10].
H19 has been proposed to play a role in the development of
glioblastoma malignancy and the maintenance of glioblastoma stem-cell
characteristics. Besides, it can promote angiogenesis, cell invasion,
and cell growth in glioma. Chen et al.[11] suggested that H19 target
miR-200a to inhibit cancer growth by interacting with CDK6 and ZEB1.
Silencing H19 was reported to increased miR-200a expression and
reduce the expression of CDK6, and subsequently inhibiting glioma cell
proliferation. [11]. HOTAIRacts as a stemness promoter by enhancing cell migration, invasion, and
proliferation in glioma. Wang et al.
[12] revealed that HOTAIR was
elevated in GBM and involved in temozolomide (TMZ) resistance. The
interaction of HOTAIR and miR-526b-3p through the epithelial
V-like antigen 1 (EVA1 ) pathway results in TMZ-resistant
GBM. Additionally, it was discovered that deleting the HOTAIRgene mitigate glioblastoma’s progression and reduced TMZ chemoresistance
[12].
There were several challenges in studying these lncRNAs. For example,
Baspinar et al. reported that many recent studies of MALAT1’s
pro-tumorigenic functions were supervised in patient-derived primary GBM
cultures rather than using established GBM cell lines such as U87,
SHG139, and U251. When compared to patient-derived primary GBM,
established cell lines can lose the inherent molecular and
pathophysiological features of the native tumour; thus, the conflicting
results could be due to cell culture errors. Nevertheless, study of
lncRNAs in glioma still merit a big good impact for glioma therapy.
Understanding the role of lncRNA in GBM or glioma pathogenesis may aid
in the development of nanoformulation and enzyme modification, such as
antisense oligonucleotides (ASOs), ribozymes, or deoxyribozymes, which
may improve the delivery of lncRNA-targeting agents into brain tumours
[10]. Recently studies discovered a
new potential lncRNA in glioma development, which is ZFAS1 .
ZNFX1 antisense RNA 1 (ZFAS1 ) islocated on chromosome
20q13.13 and can be found in both cell nucleus and cytoplasm
[13]. Recent research found thatZFAS1 expression is upregulated in many human cancers, including
glioma, lung, colon, liver, ovary, and gastric cancers, but
downregulated in breast cancer [13].ZFAS1 upregulation is associated with clinic pathological
features and prognosis, such as tumour-node-metastasis (TNM) stage,
lymph node metastasis, and overall survival in various cancers. In
addition, ZFAS1 has the potential to be utilised as a cancer
prognostic biomarker due to its vital roles in tumour progression or
cell apoptosis in a variety of human malignancies, including cervical
cancer (CC), pancreatic cancer (PC), and glioma, through modulating
mRNA, miRNA, or protein/gene expression.
[14].
A study by Su et al. [14]
reported that high ZFAS1 expression was correlated with
chemosensitivity and prognosis of CC. Overexpression of ZFAS1inhibits miR-190a-3p by sponging the miR-190a-3p and promoted the
expression of Kruppel-like factor 6 (KLF6) , which lead to CC cell
proliferation. Additionally, ZFAS1 increases CC tumor growth and
cell proliferation by upregulating LIN28 and enhanced CC cell metastasis
by sponging miR-647 [14]. Another
study by Rao et al. , [15]
described the interaction of ZFAS1 with High mobility group
protein 2 (HMGA2) and miR-497-5p in pancreatic cancer. HMGA2
upregulation promotes cell cycle entry and inhibits apoptosis, which
increases cancer cell proliferation. HMGA2 influences various DNA repair
mechanisms and promotes epithelial-to-mesenchymal transition by
activating signalling pathways such as MAPK/ERK, TGF/Smad,
PI3K/AKT/mTOR, NFkB, and STAT3. ZFAS1 was suggested to promote
HMGA2 expression through sponging miR-497-5p in PC, therefore increase
the PC development [15].
Wang et al. [16] reported thatZFAS1 was associated with advanced pathological stages and larger
tumour sizes in colorectal cancer (CRC) by regulating the synthesis of
fatty acid which can promote the malignant phenotype of CRC. Knockdown
of ZFAS1 downregulate the expression of the implicated genes to
steroid biosynthesis and fatty acid metabolism, sterol regulatory
element-binding protein 1 (SREBP1 ), fatty acid synthase
(FASN ), and stearoyl CoA desaturase 1 (SCD ) in CRC. In
addition, ZFAS1 regulates fat metabolism to promote CRC
progression by interacting with polyadenylate-binding protein 2
(PABP2 ) to facilitate the interaction of PABP2 andSREBP1 , stabilising SREBP1 mRNA and activating its
downstream genes SCD1 and FASN[16]. All of these information are
clear evidence that ZFAS1 play crucial roles in tumorigenesis.
In glioma, ZFAS1 which acts as an oncogene, with its expression
being elevated in glioma cell lines, such as U87MG, U251 and T98G, are
reported to be associated with patient outcomes and overall survival
[17]. According to Gao et al.
[18], ZFAS1 plays an oncogenic
role in glioma by regulating the Epithelial-to-Mesenchymal-Transition
(EMT) process and Notch signalling pathways. Knocking down ZFAS1inhibited EMT and Notch signalling, as well as glioma cell
proliferation, migration, and invasion. The EMT process has been shown
to be involved in cancer metastasis
[18]. Lv et al.[19] confirmed that ZFAS1expression promotes the EMT process and they discovered that knocking
down ZFAS1 decreased the expression of Matrix metalloproteinase-2
(MMP2 ), Matrix metalloproteinase-9 (MMP9 ), N-cadherin,
Integrin 1, Zinc finger E-Box binding homeobox 1 (ZEB1 ), and
significantly increased the expression of E-cadherin in glioma cells
[19].
It is currently unclear how exactly ZFAS1 is involved in
regulating gliomagenesis, as there is still a lack of understanding
regarding its role in this cancer. However, some progress has been made
in studying the mechanisms of ZFAS1 , although it is still in its
early stages in comparison to other types of cancer such as cervical,
pancreatic, and colon cancer, where ZFAS1 ’s biological functions
have been extensively investigated. Despite the limited understanding of
the regulatory mechanisms of ZFAS1 in glioma, it has been
identified as a prognostic marker and potential therapeutic target due
to its association with patient survival and glioma development
[19]. ZFAS1 further research
is needed to fully understand the role of ZFAS1 in gliomagenesis
and to develop potential therapeutic strategies targeting this lncRNA.
Hence, this scoping review was carried out with the goal of
comprehensively outlining the published research on the mechanisms ofZFAS1 in glioma and identifying any current knowledge gaps. This
review will assist our understanding of ZFAS1 ’s role in
gliomagenesis, such as its potential as a biomarker in glioma, the
importance of ZFAS1 in glioma development, the pathways and
cellular mechanisms that contribute to and affect glioma development,
and identify gaps in knowledge that will guide future research in this
discipline.