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Vol.:(0123456789)
Naunyn-Schmiedeberg's Archives of Pharmacology
https://doi.org/10.1007/s00210-024-03279-1
REVIEW
Natural products andlong noncoding RNA signatures ingallbladder
cancer: areview focuses onpathogenesis, diagnosis, anddrug
resistance
HananElimam1 · NoraA.A.Alhamshry1· AbdulrahmanHatawsh2· NourhanElfar3,4· RewanMoussa5·
AbdullahF.Radwan6· MaiA.Abd‑Elmawla7· AkramM.Elkashlan1· MohamedBakrZaki1·
MustafaAhmedAbdel‑Reheim8,9 · OsamaA.Mohammed10· AhmedSDoghish11,12
Received: 28 May 2024 / Accepted: 2 July 2024
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024
Abstract
Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs)
and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across
GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to
control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. Curcumin, baicalein, oleanolic acid,
shikonin, oxymatrine, arctigenin, liensinine, fangchinoline, and dioscin are a few examples of natural compounds that have
demonstrated promising anticancer activities against GBC through the regulation of important signaling pathways. The lncR-
NAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC,
are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR
activate oncogenes such as DNMT1, Wnt/β-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor
proteins NF-κB, EZH2, and miR-421. Clinically, specific lncRNAs can serve as diagnostic or prognostic biomarkers based
on overexpression correlating with advanced TNM stage, metastasis, chemoresistance, and poor survival. Therapeutically,
targeting aberrant lncRNAs with siRNA or antisense oligos disrupts their oncogenic signaling and inhibits GBC progression.
Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early
GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable
in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.
Keywords LncRNA· Natural products· Gallbladder cancer· Drug resistance· Diagnosis· Prognosis
* Hanan Elimam
Hanan.Elimam@fop.usc.edu.eg
* Mustafa Ahmed Abdel-Reheim
m.ahmed@su.edu.sa
1 Department ofBiochemistry, Faculty ofPharmacy,
University ofSadat City, SadatCity32897, Egypt
2 Biotechnology School, 26th ofJuly Corridor, Sheikh Zayed
City, Nile University, Giza12588, Egypt
3 School ofLife andMedical Sciences, University
ofHertfordshire Hosted byGlobal Academic Foundation,
New Administrative Capital, Cairo11578, Egypt
4 Egyptian Drug Authority (EDA), Ministry ofHealth
andPopulation, Cairo11567, Egypt
5 Faculty ofMedicine, Helwan University, Cairo11795, Egypt
6 Department ofBiochemistry, Faculty ofPharmacy, Egyptian
Russian University, Cairo11829, Egypt
7 Department ofBiochemistry, Faculty ofPharmacy, Cairo
University, Cairo, Egypt
8 Department ofPharmaceutical Sciences, College
ofPharmacy, Shaqra University, 11961Shaqra, SaudiArabia
9 Department ofPharmacology andToxicology, Faculty
ofPharmacy, Beni-Suef University, BeniSuef62521, Egypt
10 Department ofPharmacology, College ofMedicine,
University ofBisha, 61922Bisha, SaudiArabia
11 Department ofBiochemistry, Faculty ofPharmacy, Badr
University inCairo (BUC), BadrCity, Cairo11829, Egypt
12 Faculty ofPharmacy (Boys), Al-Azhar University,
NasrCity11231, Cairo, Egypt
Naunyn-Schmiedeberg's Archives of Pharmacology
Abbreviations
GBC Gallbladder cancer
lncRNAs Long noncoding RNAs
EMT Epithelial–mesenchymal transition
PRC2 Polycomb repressive complex 2
HOTAIR HOX transcript antisense RNA
XIST X-inactive specific transcript
FOXM Forkhead box protein M1
AKT2 AKT serine/threonine kinase 2
MALAT1 Metastasis-associated lung adenocarci-
noma transcript 1
EZH2 Enhancer of zeste homolog 2
LATS2 Large tumor suppressor kinase 2
NF-κB Nuclear factor kappa-light-chain-enhancer
of activated B cells
CSCs Cancer stem cells
MEG3 Maternally expressed 3
CEA Carcinoembryonic antigen
MYLK-AS1 Myosin light-chain kinase antisense RNA
1
GBCDRlnc1 Gallbladder cancer drug resistance-associ-
ated lncRNA1
MMP Matrix metalloproteinase
Dox Doxorubicin
MAPK Mitogen-activated protein kinase
AFAP1-AS1 Actin filament–associated protein 1 anti-
sense RNA 1
ANRIL Antisense noncoding RNA in the INK4
locus
BMI1 B lymphoma Mo-MLV insertion region 1
homolog
GALM GBC associated with liver metastasis
HEGBC Highly expressed in gallbladder carcinoma
H19 Imprinted maternally expressed transcript
CBX4 Chromobox4
p38 MAPK p38 mitogen-activated protein kinases
JNK c-Jun N-terminal kinase
ERK Extracellular signal-regulated kinases
MINCR Myocardial infarction–associated
transcript
NEAT1 Nuclear paraspeckle assembly transcript 1
PVT1 Plasmacytoma variant translocation 1
HK2 Hexokinase 2
SSTR5-AS1 Somatostatin receptor 5 antisense RNA 1
NONO Non-POU domain containing octamer
binding protein
ROR Regulator of reprogramming
TUG1 Taurine upregulated gene 1
CCAT1 Colon cancer associated transcript 1
FIRRE Functional intergenic repeating RNA
element
DILC Downregulated in liver cancer stem cells
DGCR5 DiGeorge syndrome critical region gene 5
ZO-1 Zonula occludens 1
FOXD2-AS1 FOXD2 adjacent opposite strand RNA 1
DNMT1 DNA methyltransferase 1
MLH1 MutL homolog 1
HGBC Highly expressed in gallbladder carcinoma
HuR Hu antigen R
HOXA-AS2 HOXA cluster antisense RNA 2
LINC00152 Long intergenic non-protein coding RNA
152
PI3K Phosphoinositide 3-kinase
UCA1 Urothelial cancer associated 1
EZH2 Enhancer of zeste homolog 2
LET Low expression in tumor
PAGBC Prognosis‐associated gallbladder cancer
SOC Suppressor of cytokine signaling
TGF Transformed growth factor
ZEB Zinc Finger E-Box Binding Homeobox
Introduction
The malignant tumor known as gallbladder cancer (GBC)
is characterized by aggressiveness and a high failure rate.
Globally, GBC is the most prevalent biliary tract cancer,
making up around two-thirds of all biliary tract cancer
cases (Krinsky 2004). Patients with advanced, incurable
GBC have a dismal median overall survival of less than 12
months and a 5-year survival rate of less than 5% due to
late-stage diagnosis and inherently aggressive disease biol-
ogy due to late-stage diagnosis, an aggressive course of the
disease, limited treatment options, and significant recurrence
rates (Hundal and Shaffer 2014, Shahin etal. 2023). Unfor-
tunately, in the early stages of the disease, the anatomical
location of the gallbladder causes non-specific symptom
presentation. More than 90% of GBC cases are diagnosed
at an advanced stage, making surgery impossible (Zou etal.
2013). Recently available cytotoxic chemotherapy regimens,
such as those involving gemcitabine and cisplatin, only mar-
ginally improve patient survival without raising quality of
life (Arslan and Yalcin 2014, Adamska etal. 2017). These
dark statistics highlight how urgently we must learn more
about the molecular pathophysiology of GBC to develop
targeted treatments.
Emerging evidence suggests that natural products from
medicinal plants and herbs may hold promise for treating
GBC by targeting key oncogenic pathways. Several natural
products such as curcumin, baicalein, oleanolic acid, shi-
konin, oxymatrine, arctigenin, liensinine, fangchinoline,
and dioscin have shown promising anticancer effects against
GBC by modulating key signaling pathways involved in pro-
liferation, apoptosis, metastasis, and drug resistance (Fig.1).
Moreover, long noncoding RNAs (lncRNAs) have become
increasingly important in the study of cancer because they
Naunyn-Schmiedeberg's Archives of Pharmacology
are complex regulators of gene expression that affect every
characteristic of malignant transformation and progression
(Tano and Akimitsu 2012, Worku etal. 2017, Wang etal.
2023). LncRNAs represent large and heterogeneous non-
protein coding transcripts exceeding 200 nucleotides gener-
ated from intergenic stretches or overlapping antisense tran-
scripts of protein-coding (Nobili etal. 2017, Mattick etal.
2023). Through dynamic interactions with DNA, RNAs, and
proteins, tens of thousands of lncRNAs—previously con-
sidered “junk DNA”—are known to participate in a variety
of biological processes (Scacalossi etal. 2019; Tyagi etal.
2018). Aberrant expression of lncRNAs is increasingly rec-
ognized as a hallmark of many cancers, orchestrating onco-
genesis through perturbed regulation of proto-oncogenes,
tumor suppressors, the cell cycle, and survival mediators
(Do and Kim 2018, Taniue and Akimitsu 2021).
Initial RNA sequencing analyses across independent
patient cohorts have demonstrated widespread dysregula-
tion of lncRNAs in GBC compared to normal gallbladder
tissue controls (Khandelwal etal. 2017, Niu etal. 2020,
Yang etal. 2023). Aberrant lncRNA expression manifests
at early preneoplastic stages and escalates with advancing
tumor progression. Functional studies have shown that lncR-
NAs interact with important signaling proteins to regulate
a variety of processes, including GBC growth, epithelial-
mesenchymal transition (EMT), invasion, metastasis, angio-
genesis, stemness, and therapeutic resistance (Jeon and Lee
2017, Hao etal. 2019, Niu etal. 2020, Hamidi etal. 2022).
Therefore, lncRNAs could serve as both attractive targets for
new GBC treatments and reliable biomarkers for diagnosis
and prognosis.
While tests for biomarkers like CEA, RCAS1, CA19-9,
CA125, CA242, and CA15-3 have been evaluated to diag-
nose GBC, they demonstrate limited sensitivity (61–87.5%).
As a result, the diagnosis and prognosis assessment of GBC
remains challenging, and it continues to have a poor prog-
nosis. Of the protein biomarkers studied, CA19-9 shows
the most promise and is advised as an important marker for
GBC diagnosis and disease monitoring. Still, more research
is warranted to improve the early detection and management
of this aggressive cancer (Shahin etal. 2023).
In this comprehensive review, we encapsulate current
concepts on lncRNA-mediated orchestration of GBC patho-
genesis, with particular emphasis on clinical translation.
Fig. 1 Widely investigated
chemical structures of natural
products
Naunyn-Schmiedeberg's Archives of Pharmacology
We outline lncRNA biogenesis, functional taxonomy, and
mechanisms enabling gene expression control in GBC cells.
Next, we detail major natural products and lncRNAs steer-
ing GBC growth, dissemination, and therapeutic resistance
through the regulation of pivotal onco- and tumor suppressor
proteins. Finally, we appraise the diagnostic, prognostic, and
therapeutic opportunities conferred by lncRNA signatures at
tissue and circulating levels to combat this lethal malignancy
through precision medicine approaches.
Natural products andGBC
Curcumin
Curcumin is an extract from turmeric and a naturally occur-
ring phytochemical. Clinical trials on curcumin have been
conducted on the basis of an array of invitro and invivo
evidence. Important signaling pathways involved in cellu-
lar functions are modulated by curcumin. Curcumin may
act as a multitarget medication because it can alter several
cellular pathways implicated in the development of cancer.
This has special relevance to the treatment of neoplastic
diseases (Irving etal. 2011, Gupta etal. 2013). Ono etal.
elucidated that curcumin exerts beneficial effects in GBC
through several mechanisms, including decreased Bcl-2
function, decreased AKT-mTOR activity, and increased
mitogen-activated protein (MAP) kinase activity, and pro-
motes G2/M arrest (Ono etal. 2013a). These findings offer
a molecular explanation for curcumin’s possible application
in the management of GBC. Another study investigated
that curcumin controls the Bcl-2/Bax ratio and triggers
the production of cleaved caspase-3, leading to apoptosis
in GBC-SD cells (Liu etal. 2013). Depending on the sig-
nal transduction mechanisms that are activated, curcumin
displays varying activities against apoptosis and cell cycle
progression. Additionally, curcumin can block downstream
signaling pathways that are activated by Src and Ras, indi-
cating that it may be useful in treating human cancers that
have activated Src or Ras (Ono etal. 2013b). Additionally,
curcumin lowered the expression of CXCR4 invitro and
invivo, which likely decreased metastasis by suppressing
the stromal cell–derived factor-1/CXCR4 signaling pathway
(Gu etal. 2019).
Baicalein
Baicalein is widely used and has a variety of pharmacologi-
cal actions. GBC cell metastasis was suppressed by baicalein
treatment. Moreover, baicalein inhibited GBC cell growth
and metastasis via downregulation of zinc finger protein
X-linked (ZFX) expression (Liu etal. 2015). By focusing on
the PTEN/PI3K/AKT signaling pathway, sinensetin flavone
has been shown to demonstrate strong anticancer efficacy
against drug-resistant human GBC through the former axis
(Huang etal. 2020). Song and his colleagues reported that
the flavone casticin causes G0/G1 arrest and apoptosis in
GBC and that casticin may be a new and useful treatment
for this disease (Song etal. 2017b). Concurrently, the fla-
vone hispidulin exhibits anti-malignant effects on GBC by
inhibiting HIF-1α signaling. Hispidulin attenuates the resist-
ance to chemotherapeutic drugs such as gemcitabine and
5-fluorouracil by downregulating HIF-1α (Gao etal. 2015).
The flavonoid icariin exhibits anticancer action and enhances
the antitumor activity of gemcitabine in GBC by inhibiting
NF-κB activity. For patients with GBC, the combination of
gemcitabine and icariin may provide a more effective course
of treatment (Zhang etal. 2013). It was documented that the
flavonoid isorhamnetin inhibited the growth and spread of
GBC cells, induced apoptosis, and stopped the G2/M phase
in GBC cells by blocking the PI3K/AKT signaling pathway
(Zhai etal. 2021).
Triterpenoids
Triterpenoids are natural compounds that are formed by the
cyclization of squalene, resulting in the production of either
3-deoxytriterpenes (hydrocarbons) or 3-hydroxytriterpenes.
Triterpenoids are derived from two categories of triterpenes
by the process of modifying their carbon framework to yield
oleanolic acid, pachymic acid, and shikonin. Triterpenoids
are extensively found in higher plants and are significant
due to their diverse structures and wide variety of biological
functions (Özdemir and Wimmer 2022, Zang etal. 2022).
Oleanolic acid, a naturally derived triterpenoid, demon-
strates promising anticancer effects in many types of tumor
cell lines. Oleanolic acid effectively suppresses the growth
of GBC cells in a way that is influenced by both the dos-
age and duration of treatment. This study provided evidence
that oleanolic acid operates via the mitochondrial apoptotic
pathway. Furthermore, this medication suppressed the pro-
liferation of tumors in nude mice and hindered the growth
of GBC cells via controlling apoptosis and the cell cycle
process. Therefore, oleanolic acid shows potential as a ben-
eficial medication for adjuvant chemotherapy in gallblad-
der malignancies (Tang etal. 2022). In another study, the
impact of pachymic acid on tumors in human GBC cells
was investigated. This study demonstrated that pachymic
acid has the ability to suppress the development of GBC
via affecting the AKT and ERK signaling pathways. These
findings support pachymic acid as a potential treatment for
GBC (Chen etal. 2015). In addition, shikonin, a naturally
occurring compound obtained from the roots of Lithosper-
mum erythrorhizon, is known for its anticancer properties. It
was found that shikonin decreased the growth of GBC cells.
Additionally, it induced apoptosis and caused G0/G1 phase
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arrest in the GBC cells through the JNK signaling pathway.
These findings demonstrate that shikonin has anticancer
properties on GBC cells through the stimulation of apopto-
sis and modulation of the cell cycle. Collectively, shikonin
has the potential to serve as a new and secure chemotherapy
drug for the management of GBC (Zhai etal. 2017, Wang
etal. 2020a).
Alkaloids
Alkaloids are chemical compounds that play an important
role in developing innovative medications since they provide
a rich resource for creating these new medicines. Studies
conducted on a variety of cancers, both invitro and invivo,
have shown promising outcomes for a number of alkaloids
that are derived from medicinal plants and herbs (Mondal
etal. 2019). Through research conducted both in the lab-
oratory and on animals, oxymatrine (OM) was shown to
have a potent anticancer effect on cells derived from GBC.
Additionally, it is believed that the anticancer benefits of
OM are likely derived from its ability to limit cell growth
and promote programmed cell death. The downregulation
of NF-κB expression and the activation of the mitochon-
dria-mediated apoptotic pathway are both necessary steps
in order to accomplish this (Wu etal. 2014b). Arctigenin,
which is derived from the seeds of Centaurea schischkinii,
was shown to have potent cytotoxic effects on CaCo-2 colon
cancer cell lines, according to the findings of an independent
analysis. Arctigenin was shown to be responsible for a sig-
nificant reduction in the expression of EGFR in GBC tissue,
which in turn led to the induction of cellular senescence. For
this purpose, the RAF-MEK-ERK signaling pathway was
altered. The results of these experiments showed that the
suppression of EGFR led to the cessation of cell division
during the G1/G0 phase and the induction of programmed
cell death (Zhang etal. 2017a).
Experiments conducted invitro and invivo demonstrated
that liensinine has a substantial impact on reducing GBC
cell proliferation. The effects of lisinine on cell growth and
proliferation invitro were dose- and time-dependent and
demonstrated a considerable reduction in both of these pro-
cesses. Lisinine was able to effectively suppress the forma-
tion of tumors invivo environments. A study conducted by
Shen etal. suggests that lisinine has the potential to cause
GBC cells to shut down in the G2/M phase. This is accom-
plished by increasing the quantities of CDK1 and Cyclin B1
protein in the body. Through the inhibition of the expression
of essential proteins such as AKT, p-AKT, PI3K, and ZFX,
Liensinine was able to have an impact on the advancement
of the GBC cell cycle and apoptosis rates (Shen etal. 2019).
Finally, it was shown by Li etal. that fangchinoline,
which is a bisbenzylisoquinoline alkaloid, inhibits the
growth and reproduction of GBC cells in a dose-dependent
manner. The results of flow cytometry, TUNEL staining,
and Hoechst staining gave further proof that fangchinoline
is capable of inducing cell death in GBCs. In GBC cells,
the anti-apoptotic PI3K/Akt/XIAP axis was significantly
suppressed by fangchinoline treatment, as shown by further
research (Li etal. 2022a).
Phenolic compounds
In the last 10 years, the antioxidant properties of dietary
plant polyphenols have garnered considerable attention for
their possible positive effects on health. Epidemiological
studies and meta-analyses have shown that a diet rich in
plant polyphenols reduces the risk of cancer, heart disease,
diabetes, osteoporosis, and neurological disorders when fol-
lowed over the long term. There is strong epidemiological
evidence that phenolics have anticarcinogenic, anti-inflam-
matory, and antioxidant properties, which make them pow-
erful tools in the fight against chronic diseases (Rahman
etal. 2022).
While both the crude and anthocyanin-rich Calafate fruit
extracts exhibited a reduction in the migratory potential and
invitro viability of gallbladder (G415) and stomach (AGS)
cancer cell lines, the anthocyanin-rich extract showed much
greater efficacy. The significant presence of delphinidin in
this extract, which is recognized for its potent antioxidant
properties in comparison to those of other phenolic and
anthocyanidin chemicals, is likely the primary factor con-
tributing to this discovery. Hence, the findings of this study
provide significant insights for future research, indicating
that Calafate fruits might serve as a valuable resource for
the creation of phytopharmaceutical compounds to address
human health concerns. To get a deeper understanding of
the positive impacts of Calafate fruits and their natural
components, such as phenolics or alkaloids that likely work
together in a favorable way, it is necessary to undertake a
comprehensive analysis of the secondary metabolites found
in the crude and anthocyanin-rich extracts of these fruits
(Calderón-Reyes etal. 2020).
Tea polyphenols (TPs) possess anti-inflammatory proper-
ties, combat cancer, inhibit blood clot formation, eradicate
microorganisms, and promote vasodilation. Wang etal. dis-
covered that TPs had a strong inhibitory effect on the prolif-
eration of GBC cells both invivo and invitro. Researchers
examined the impact of TPs on GBC cell apoptosis and cell
cycle arrest, which are two important indications of anti-
cancer activity. TPs may induce apoptosis that is associated
with mitochondria and halt the cell cycle of GBC cells in
the S phase. Furthermore, the research revealed that TPs
did not have any detrimental effects on healthy gallblad-
der cells. Based on their research, it has been shown that
TPs are harmless chemicals that have great promise for
treating GBC. The mitochondrial membrane potential of
Naunyn-Schmiedeberg's Archives of Pharmacology
NOZ-treated cells was also reduced after 48 h of TP treat-
ment, indicating that apoptosis linked to mitochondria con-
tributed to the demise of GBC cells. The expression of Bax
and Bcl2 was upregulated and downregulated, respectively,
after TP treatment. The release of cytochrome c into the
cytosol increased, whereas the membrane potential of the
mitochondria decreased, which was associated with altera-
tions in protein expression. Following treatment with TPs,
there was an observed rise in levels of cleaved caspase-3
and PARP. The Caspases family has a role in mitochondria-
induced apoptosis (Wang etal. 2018).
Numerous biological and pharmacological effects have
been shown for Dioscin (DSN), a plant glucoside sapo-
nin derived from Dioscorea zingiberensis Wright and
Dioscorea nipponica Makino. The anti-fungal, anti-viral,
and hepatoprotective effects of DSN have been shown in
earlier research. Because of its anticancer benefits on lung,
colon, breast, and stomach cancers, DSN has lately garnered
much interest. The review findings demonstrated that DSN
effectively halted the migration and proliferation of GBC
cells. In addition, DSN caused GBC cell death via means
of apoptotic signaling that relies on mitochondria. Tests
for glutathione (GSH) and reactive oxygen species (ROS)
showed that ROS scavengers entirely blocked DSN-induced
migration and apoptosis, suggesting that ROS are critical for
the development of gastric cancer. Analysis using Western
blotting demonstrated a significant decrease in AKT activity
after DSN administration. Furthermore, it was shown that
AKT apoptosis, but not migration, was boosted or abolished
when AKT was either inhibited or expressed ectopically.
Additionally, the research demonstrated that ROS are related
to the PI3K/AKT pathway and that DSN caused cell death
by controlling ROS-mediated PI3K/AKT signaling (Song
etal. 2017a).
The molecular choreography oflncRNA biogenesis
andfunction
LncRNAs are a diverse class of RNA transcripts longer than
200 nucleotides that are transcribed by RNA polymerase II
but do encode proteins (Mattick etal. 2023). The genomic
organization of lncRNA genes is similar to that of protein-
coding genes; both have 3′ poly(A) tails and exons, introns,
and 5′ caps (Ulitsky and Bartel 2013, Statello etal. 2020).
However, because they do not contain open reading frames,
lncRNAs avoid being translated into amino acid sequences.
Rather, complex molecular interactions involving proteins,
RNAs, and DNA enable lncRNAs to control the gene expres-
sion patterns that underpin tissue homeostasis, cell differ-
entiation, and embryonic development (Mangiavacchi etal.
2023). Aberrant lncRNA expression features prominently
across human cancer transcriptomes, with mutations in criti-
cal lncRNA loci implicated as driver events in tumorigenesis
(Jiang etal. 2019). Therefore, understanding the unique bio-
synthesis pathways and molecular mechanisms controlling
the functionality of lncRNAs can provide insights into both
healthy and diseased states of biology.
LncRNA biogenic pathways
LncRNA regulation has been shown to play important roles
in several classical pathways. The majority of these canoni-
cal pathways involve direct mechanisms connected to tran-
scriptional, post-transcriptional, and chromatin processes
(Fig.2). One major canonical pathway involves lncRNAs
regulating gene expression by interacting with chromatin
remodeling complexes to alter chromatin state and acces-
sibility. Chromosome accessibility and structure modula-
tion by lncRNAs enable them to affect subsequent genetic
programs. For example, in female placental mammals, the
lncRNA XIST coats and modifies one X chromosome’s
chromatin state to carry out the essential function of X
chromosome inactivation (Li etal. 2022b). The Polycomb
repressive complex 2 (PRC2), which sets down repressive
histone marks along chromosomes, is one of the chromatin
remodeling complexes that are recruited by XIST (Shi etal.
2017, Colognori etal. 2019).
Another example includes the lncRNA HOTAIR which
silences chromosomal domains by binding to and scaffold-
ing between PRC2 and LSD1 histone-modifying complexes,
enabling coordinated histone H3 lysine 27 trimethylation
and lysine 4 demethylation (Hajjari and Salavaty 2015,
Pawłowska etal. 2017). Additional illustrations of this
canonical pathway include lncRNAs that guide chroma-
tin modifiers, like PRC2, or histone-modifying enzymes
to specific genomic loci resulting in activation or silenc-
ing, respectively (Meseure etal. 2015, Zhang etal. 2021).
In addition to manipulating chromatin, lncRNAs are also
known to directly regulate gene expression at the transcrip-
tional level by interacting with key transcription factors and
other components of the basic transcriptional machinery.
For example, the lncRNA Evf-2 works cooperatively with
the homeodomain protein Dlx2 to form an activating com-
plex that induces transcription of downstream target genes
involved in important neural development pathways (Kaik-
konen etal. 2011). Lastly, another important mechanism
by which lncRNAs regulate gene expression is the complex
post-transcriptional regulation of RNA processing, transport,
stability, and translation (Kung etal. 2013, Doghish etal.
2024b).
In contrast to these widely described canonical inter-
actors and pathways, studies have also uncovered non-
canonical modes by which lncRNAs execute important
cellular functions. These non-traditional mechanisms dem-
onstrate the remarkable versatility of lncRNA signaling.
Through a variety of allosteric and stochastic interactions,
Naunyn-Schmiedeberg's Archives of Pharmacology
cytoplasmic and nuclear lncRNAs have emerged as impor-
tant modulators of protein activity instead of directly
affecting local chromatin or transcription (Guh etal.
2020). For instance, conformational changes induced upon
lncRNA binding can unlock inactive states of proteins, as
demonstrated by the lncRNA which binds to TLS, mak-
ing TLS undergo a conformational shift that enables its
amino terminus to block p300 and CBP’s histone acetyl-
transferase activity, which in turn suppresses gene expres-
sion (Fu 2014). Conversely, lncRNAs can obstruct active
sites or disrupt multimerization interfaces, as exemplified
by MEG3 binding and repressing p53 tetramerization to
attenuate downstream signaling (Zhang etal. 2023). Fur-
thermore, lncRNAs have emerged as critical controllers of
cellular pathways by acting as molecular decoys that soak
up protein or RNA regulators (Gao etal. 2020, Giuliani
etal. 2023). For example, NORAD sequesters PUMILIO
proteins to influence mitotic progression by acting as a
potent stoichiometric sponge (Schmitt and Chang 2016,
Liu and Chen 2022). By covering binding sites, cytoplas-
mic long noncoding RNAs (lncRNAs) like 1/2-sbsRNAs
can function as mRNA masks, preventing microRNA-
directed cleavage of transcripts associated with funda-
mental metabolism (Jafari-Raddani etal. 2022). Overall,
by titrating away regulators from intended targets, these
lncRNA decoys provide a customizable buffering system
to fine-tune pathways.
For example, cytoplasmic lncRNAs harbor binding sites
that sequester miRNAs away from their mRNA targets as
competitive “sponges” to impart an additional layer of tar-
get specificity (43). Other examples include lncRNAs that
interact with spliceosome machinery components to directly
modulate splicing and change the isoform expression of cru-
cial genes (44). Collectively, through interacting with vari-
ous RNA and protein regulators, lncRNAs hold vital roles in
cohesively ensuring proper mRNA and protein production.
LncRNA functions
LncRNAs carry out a multitude of gene regulatory functions
through diverse molecular mechanisms across numerous
cancers such as CRC, breast cancer, gastric cancer, and lung
cancer. They can serve as decoys to bind and sequester pro-
teins or microRNAs, act as scaffolds to bring together multi-
ple regulatory components, and guide chromatin and protein
complexes to target genes (Ratti etal. 2020). Through these
mechanisms, lncRNAs control transcriptional programs,
modulate chromatin architecture, and regulate down-
stream gene expression (Alvarez-Dominguez and Lodish
2017). The dysregulated expression of lncRNAs promotes
Fig. 2 LncRNAs have a crucial impact on the alteration and control
of gene expression. LncRNAs exert influence on mRNA stability
in various ways. Examples include direct binding to target mRNAs,
interactions with RNA-binding proteins, competition with miR-
NAs as competing endogenous RNAs, regulation of mRNA decay
pathways, and interference with transcription. LncRNAs can finely
regulate gene expression after transcription by either stabilizing or
degrading certain mRNAs.
Naunyn-Schmiedeberg's Archives of Pharmacology
tumorigenesis by stimulating proliferation, invasion, metas-
tasis, angiogenesis, immune evasion, and drug resistance
(Zhou etal. 2022). Cancer-specific lncRNA expression pat-
terns make them attractive biomarker candidates (Eptam-
initaki etal. 2022). Knockdown of oncogenic lncRNAs can
inhibit cancer growth and viability (Tsai etal. 2018). In
GBC, lncRNAs such as HOTAIR, H19, and MALAT1 are
overexpressed and drive oncogenesis by altering prolifera-
tion, chemoresistance, and metastasis (Pérez-Moreno etal.
2021, Schwerdtfeger etal. 2021). Overall, lncRNAs are criti-
cal gene regulators and play indispensable functional roles
in the initiation, progression, and metastasis of numerous
cancers, including GBC.
Role oflncRNAs inthepathogenesis ofGBC
Prior research has demonstrated the important involvement
of lncRNAs in the biology of cancer, and abnormalities
in lncRNAs are linked to several forms of human malig-
nancies. So far, a considerable number of lncRNAs have
been described to be involved with GBC (Pérez-Moreno
etal. 2021, Doghish etal. 2024a). Here the review article
demonstrated the effect of lncRNA expression alterations on
the pathogenesis of GBC.
Upregulated lncRNAs inGBC
Many lncRNAs have been identified to participate in GBC
pathogenesis through many pathways. Gao et. al found that
the lncRNA FOXD2-AS1 is capable of recruiting the meth-
yltransferase DNMT1 to the promoter region of the MLH1
gene, leading to the suppression of MLH1 transcription.
This process ultimately speeds up the advancement of GBC
(Gao etal. 2021b) (Fig.3). Another study revealed that gall-
bladder cancer stem cells (CSCs) and GBC tissues expressed
higher levels of DILC, leading to the enhancement of self-
generation, tumorigenicity, proliferation, and metastasis. In
addition, DILC facilitated the progression of GBC cells by
stimulating the Wnt/β-catenin signaling pathway. LncRNA
DILC enhances the Wnt/β-catenin signaling pathway by pro-
moting the stability and nuclear translocation of β-catenin.
This leads to increased transcriptional activity of β-catenin/
TCF complexes, driving the expression of genes that pro-
mote GBC cell proliferation, self-renewal, and metastasis
(Liang etal. 2019) (Fig.3).
Fig. 3 Regulatory mechanism involving lncRNA FOXD2-AS1,
DILC, and HGBC in GBC. lncRNA FOXD2-AS1 blocks MLH1 tran-
scription by binding the methyltransferase DNMT1 to its promoter.
This accelerates GBC. Gallbladder CSCs and GBC tissues produced
more DILC, enhancing self-generation, tumorigenicity, proliferation,
and metastasis. DILC also promoted GBC cell growth by activat-
ing the Wnt/β-catenin signaling pathway. LncRNA-HGBC sponging
miR-502-3p promotes GBC cell growth and metastasis. Blocking
miR-502-3p promotes SET expression, which activates AKT signal-
ing.
Naunyn-Schmiedeberg's Archives of Pharmacology
HOXA-AS2, a lncRNA located inside the HOXA cluster
between the HOXA3 and HOXA4 genes, has been identi-
fied as a promoter in many types of cancer, such as acute
promyelocytic leukemia and gastric cancer. Suppression
of HOXA-AS2 may hinder cell proliferation and trigger
apoptosis (Zhao etal. 2013). The HOXA-AS2 lncRNA
was shown to be highly upregulated in GBC tumor tissues.
Furthermore, the upregulation of HOXA-AS2 was shown
to be linked to the advancement of GBC. Suppression of
HOXA-AS2 hampers the ability of GBC cell lines to invade
and metastasize via modulating the EMT pathway. In cells
overexpressing lncRNA HOXA-AS2, the expression of
E-cadherin was reduced, while the expression of vimentin
and N-cadherin was increased. This suggests that the effects
of HOXA-AS2 on cell migration and invasion are partially
related to the process of EMT in GBC (Zhang etal. 2017b).
According to Hu etal., LncRNA-HGBC stabilized by
HuR promotes the growth of GBC by controlling the miR-
502-3p/SET/AKT axis. LncRNA-HGBC acts by sponging
miR-502-3p to induce GBC cell proliferation and metasta-
sis. Blocking miR-502-3p increases the expression of SET,
which in turn triggers the activation of AKT signaling. This
ultimately leads to the advancement of cancer. The latest
research establishes that the lncRNA-HGBC/miR-502-3p/
SET/AKT pathway has a significant impact on the course
of GBC. This highlights lncRNA-HGBC as a promising tar-
get for therapeutic interventions in GBC (Hu etal. 2019b).
Another study that examined the function of the DiGeorge
syndrome critical region gene (DGCR5) in GBC revealed
that by sponging miR-3619-5p and activating the JNK/p38
MAPK and MEK/ERK1/2 pathways, DGCR5 promotes
GBC cell invasion, proliferation, and migration (Liu etal.
2020c) (Fig.4 and Table1).
In GBC tissues, there was a rise in CCAT1 expression.
Suppression of CCAT1 reduced the target gene Bmi1’s
expression, whereas overexpression of CCAT1 increased
its expression by competitively binding to miRNA-218-5p.
Downregulation of CCAT1 hindered the growth and inva-
sive properties of GBC cells, perhaps by interfering with the
miRNA-218-5p-mediated control of Bmi1 (Ma etal. 2015b).
Researchers found that lncRNA GBCDRlnc1 interacts with
PGK1 and prevents its depletion, which causes an upregu-
lation of ATG5-ATG12 expression, therefore promoting
autophagy and drug resistance in GBC cells. Hence, target-
ing the GBCDRlnc1/PGK1/ATG5-ATG12 conjugate signal-
ing pathway should serve as a promising treatment strategy
for chemotherapy in GBC (Cai etal. 2019a).
HOTAIR has higher expression levels in GBC tissues
compared to safety margin non-tumoral tissues, suggest-
ing that HOTAIR is often elevated in GBC. Furthermore,
HOTAIR is more prominently present in GBC classified as
T3 or T4, as opposed to tumors classified as T1 or T2. The
expression of HOTAIR is more pronounced in tumors that
have progressed to regional lymph nodes (N1) versus origi-
nal tumors. This suggests that HOTAIR expression might
serve as a diagnostic marker for the course and prognosis
of GBC patients. HOTAIR enhances the growth and move-
ment of GBC cell lines, showing a positive association with
c-Myc expression and a negative association with miRNA-
130a. This indicates that this mechanism may contribute to
the advancement of cancer in GBC patients (Ma etal. 2014).
Downregulated lncRNAs inGBC
The lncRNA MEG3 suppresses the proliferation and induces
apoptosis in human GBC cells invitro. Moreover, it plays
a crucial role in regulating the progression of GBC. Tar-
geting the lncRNA MEG3 might act as a novel treatment
approach for GBC. The lncRNA MEG3 interacts with the
tumor-inhibiting gene p53 and controls the production of
p53 target genes by directly modifying the activity of the
p53 promoter (Bao etal. 2020) (Table1).
The expression of GATA6-AS was considerably reduced
in GBC tissues, and the overexpression of GATA6-AS led
to the suppression of cancer cell migration and invasion.
Hence, in addition to promoting cell proliferation, GATA6-
AS may also modulate several cellular activities, contribut-
ing to cancer biology. GATA6-AS is a probable regulator
that acts before miR-421 to limit its activity in GBC cells.
There are reports indicating that the levels of miR-421 may
be controlled by certain lncRNAsduring the progression of
cancer (Li etal. 2019b).
A clear decrease in the expression of lncRNA-LET was
identified in GBC in comparison to the surrounding normal
tissues. Conversely, those who have low levels of lncRNA-
LET have a notably worse prognosis compared to those with
high levels. Furthermore, the upregulation of lncRNA-LET
was confirmed to effectively hinder the invasion of GBC
cells invitro, both in hypoxic and in normoxic conditions.
The overexpression of lncRNA-LET was shown to provide
a growth advantage to tumor cells in low-oxygen environ-
ments. Overexpression of lncRNA-LET resulted in the
enhancement of cell cycle arrest specifically, in the G0/
G1 phase, and the initiation of programmed cell death in
hypoxic environments. Overexpression of LncRNA-LET
prevented GBC from growing invivo (Ma etal. 2015a).
Role oflncRNAs intheprogression andmetastasis
ofGBC
In GBC tissues and cell lines, PVT1 upregulation and miR-
30d-5p downregulation were detected. Suppression of PVT1
led to a reduction in cellular proliferation and invasion in
GBC cells. The targeting of miR-30d-5p by PVT1 was
confirmed, and there was a negative correlation observed
between their expression in GBC tissues. Moreover, PVT1
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sponges miR-30d-5p, which raises downstream factor
HDAC9 expression and helps cancer cells function more
easily. The inhibition of miR-30d-5p might counteract the
consequences of PVT1 knockdown. PVT1 contributed to the
development of GBC via stimulating cell growth and inva-
sion through the action of miR-30d-5p. This suggests that
PVT1 may be a useful biomarker for the identification and
treatment of GBC (Liu and Xu 2020) (Fig.5 and Table2).
Knocking down Linc-ITGB1 resulted in a considerable
decline in the growth of GBC cells and showed a substantial
decrease in cell migration and invasion, which was prob-
ably due to a rise in β-catenin and a fall in TCF8, slug, and
vimentin. The acceleration of EMT by inc-ITGB1 could
contribute to the invasion and spread of GBC. In advanced-
stage patients, RNA interference that targets linc-ITGB1
may be a viable therapeutic approach (Wang etal. 2015)
(Fig.5 and Table2).
The lncRNA-HGBC, which exhibited upregulation in
GBC tissue, was predictive of an unfavorable prognosis
regarding survival. In cell lines of GBC, overexpression
Fig. 4 Regulatory mechanism involving lncRNA DGCR5 in GBC. DiGeorge syndrome critical region gene (DGCR5) induces GBC cell inva-
sion, proliferation, and migration by sponging miR-3619-5p and activating the JNK/p38 MAPK and MEK/ERK1/2 pathways.
Naunyn-Schmiedeberg's Archives of Pharmacology
of lncRNA-HGBC led to a corresponding elevation in cel-
lular replication and infiltration in laboratory settings and
implanted malignancies. LncRNA-HGBC exhibited specific
binding to HuR, which served to stabilize HGBC. Addition-
ally, HGBC binds to miR-502-3p to generate a competitive
endogenous RNA, which inhibits (Hu etal. 2019a).
Suppression of KIAA0125 greatly reduced cellu-
lar migration and invasion. Moreover, after suppressing
KIAA0125, GBC-SD/M cells exhibited reduced vimentin
and increased β-catenin levels. Thus, the results indicate that
KIAA0125 might function as a potential target for treatment
in advanced GBC, as it promotes the migration and invasion
of GBC cells (Lv etal. 2015) (Fig.5 and Table2).
The expression of the lncRNA-ROR was increased in
GBC tissues and a robust relationship existed between
elevated expression of LncRNA-ROR and a worse progno-
sis in individuals with GBC. Furthermore, cellular prolif-
eration, migration, and invasion were hampered by ROR
suppression. The EMT phenotype caused by TGF-1 was
reversed in SGC-996 and Noz cells after lncRNA-ROR was
knocked down. LncRNA-ROR performs a critical function
in the advancement of GBC by facilitating the EMT in this
kind of cancer. LncRNA-ROR might be used as a target for
therapeutic interventions and a prognostic indicator in GBC
(Wang etal. 2016d).
SPRY4-IT1 was found to be overexpressed in GBC
tissues. Knocking down SPRY4-IT1 greatly reduced
GBC cell growth. Moreover, the suppressive impact of
SPRY4-IT1 on cellular migration and invasion has been
linked to the EMT process (Yang etal. 2017). Tissue
Table 1 Characteristics of lncRNAs in the pathogenesis of GBC
LncRNA Alteration Function Ref.
FOXD2-AS1 Upregulated Suppression of MLH1 transcription. Gao etal. (2021b)
DILC Stimulating Wnt/β-catenin. Liang etal. (2019)
HOXA-AS2 Modulating EMT. Zhang etal. (2017b)
LncRNA-HGBC Regulating miR-502-3p/SET/AKT axis. Hu etal. (2019b)
DGCR5 stimulating MEK/ ERK1/2 and JNK/p38 MAPK. Liu etal. (2020c)
CCAT1 competitively binding to miRNA-218-5p. Ma etal. (2015b)
GBCDRlnc1 GBCDRlnc1/PGK1/ATG5-ATG12 axis. Cai etal. (2019a)
HOTAIR Positive association with c-Myc expression and a negative association with miRNA-
130a.
Ma etal. (2014)
MEG3 Downregulated Directly modifying the activity of the p53 promoter. Bao etal. (2020)
GATA6-AS GATA6-AS is a probable regulator that acts before miR-421 to limit its activity in
GBC.
Li etal. (2019b)
LET Cell cycle arrest specifically, in the G0/G1 phase, and the initiation of programmed
cell death in hypoxic environments.
Ma etal. (2015a)
Fig. 5 Role of lncRNAs in the
progression and metastasis of
GBC
Naunyn-Schmiedeberg's Archives of Pharmacology
samples from GBC demonstrated a substantial rise in
TUG1 expression. Studies demonstrated that suppress-
ing TUG1 drastically decreased the proliferation and
spread of GBC cells. TUG1 is stimulated by TGF-β1.
Additionally, when TUG1 was suppressed, it resulted in
the prevention of EMT in GBC cells. Furthermore, it has
been shown that TUG1 exerts a deleterious impact on the
expression of miR-300, a molecule known to function as
a suppressor in a range of malignancies (Ma etal. 2017).
Although the precise lncRNA’s principal functions in
GBC have yet to be determined, researchers have shown
that they are important regulators in the growth and devel-
opment of GBC (Wang etal. 2016a). MALAT1 promotes,
by activating the ERK/MAPK pathway, the proliferation
and metastasis of GBC cells (Wu etal. 2014a) (Fig.5 and
Table2). Furthermore, lncRNA HOTAIR also contributes
to GBC metastasis and progression through c-myc activation
of malignancy and downregulation of miRNA-130a in GBC
(Gupta etal. 2010). Due to lncRNA-LET downregulation
when GBC spreads and metastasizes, it is considered a prog-
nostic biomarker in GBC (Ma etal. 2015d). Additionally,
by competitively sponging miRNA-218-5p, lncRNA
CCAT1 promotes the expression of Bmi1, the target gene
of miRNA-218-5p, which in turn promotes the formation
of GBC (Ma etal. 2015a). Moreover, through the pathway
of Wnt/β-catenin, lncRNA DILC accelerates the progres-
sion and metastasis of GBC (Li etal. 2019a). Along with
the previously mentioned lncRNAs, DGCR5 is the lncRNA
linked to invasion, growth, invasion, migration, and prolif-
eration in GBC invivo. It does this by downregulating ZO-1
and E-cadherin expression and upregulating N-cadherin,
vimentin, MMP-2, and MMP-9 expression levels via the
MEK/ERK1/2 and JNK/p38 MAPK axes (Liu etal. 2020b).
An additional lncRNA linked to the emergence of aggres-
sive characteristics in cancer is FOXD2-AS1, which has
been shown to induce proliferation and metastasis in GBC
because it has the ability to captivate DNMT1, a methyl-
transferase that subsequently methylates the MLH1 gene’s
promoter, thereby inhibiting MLH1 transcription (Gao etal.
2021a). H19 expression in GBC has been shown to be higher
in malignant tissue than in adjacent non-tumor tissue. By
sponging the miRNAs in the axes of H19/miR-342-3p/
Table 2 Role of lncRNAs in the progression and metastasis of GBC
LncRNA Expression Function Mechanism Ref.
PVT1 Up Stimulate cell growth and invasion miR-30d-5p downregulation Liu and Xu (2020)
Linc-ITGB1 Up Acceleration of EMT Decreased β-catenin and increased TCF8,
slug, and vimentin levels
Wang etal. (2015)
HGBC Up Elevation in cellular replication and infiltra-
tion
HGBC binds to miR-502-3p to generate a
competitive endogenous RNA
Hu etal. (2019a)
KIAA0125 Up Promotes the invasion and migration Reduced β-catenin and increased vimentin
levels
Lv etal. (2015)
Lnc-ROR Up Promotes cellular proliferation, migration,
invasion, and EMT
Not detected Wang etal. (2016d)
SPRY4-IT1 Up Promotes migration, invasion, and EMT
process
Not detected Yang etal. (2017)
TUG1 Up Promotes migration, invasion, and EMT
process
Exerts a deleterious impact on the expression
of miR-300
Ma etal. (2017)
MALAT1 Up Promotes the proliferation and metastasis Stimulating ERK/MAPK Wang etal. (2016a)
HOTAIR Up Contributes to metastasis and progression c-myc activation of malignancy and down-
regulation of miRNA-130a
Gupta etal. (2010)
LET Down It facilitates GBC to spread and metastasize Not determined Ma etal. (2015d)
CCAT1 Up Encourages the development and metastasis
of GBC
Escalates the expression of the Bmi1 gene by
miRNA-218-5p sponging
Ma etal. (2015a)
DILC Up Accelerates the progression and metastasis Wnt/β-catenin pathway activation Li etal. (2019a)
DGCR5 Up Promotes proliferation, migration, invasion,
and growth in GBC
Through enhancing the JNK/p38 MAPK and
MEK/ERK1/2 routes
Liu etal. (2020b)
FOXD2-AS1 Up Inhibiting MLH1 gene transcription Gao etal. (2021a)
H19 Up Associated with larger tumors, lymphatic
metastases, and a worse prognosis
Sponging the miRNAs in the axes of H19/
miR-342-3p/FOXM1 and H19/miR-194-5p/
AKT2
Wang etal. (2016b),
Wang etal.
(2016c)
GATA6-AS Down Induce proliferation and metastasis Sponging miR-421 Li etal. (2019a)
MEG3 Down Exacerbates the prognosis and metastasis By controlling the NF-κb pathway, ubiquit-
inating EZH2, and suppressing large tumor
suppressor 2 (LATS2)
Jin etal. (2018)
Naunyn-Schmiedeberg's Archives of Pharmacology
FOXM1 and H19/miR-194-5p/AKT2, its expression is
linked to bigger tumors, lymphatic metastases, and a worse
prognosis in patients with GBC (Wang etal. 2016b, Wang
etal. 2016c). LncRNAs that are downregulated during the
progression and metastasis of GBC are GATA6-AS and
MEG3. GATA6-AS has been shown to decrease progres-
sively in GBC advanced stages by downregulating miR-421
(Li etal. 2019a). On the other hand, poor MEG3 expression
exacerbates the prognosis and metastasis by controlling the
NF-κB pathway, ubiquitinating EZH2, and suppressing large
tumor suppressor 2 (LATS2) (Jin etal. 2018).
Role oflncRNAs indrug resistance
Since GBC is the most severe kind of cancer that may
affect the biliary tract, individuals with unresectable GBC
need intensive treatment. Nonetheless, physicians continue
to face difficulties with chemotherapy resistance (Lai etal.
2023). LncRNAs are involved not only in the etiology and
prognosis of GBC but also in the positive or negative reg-
ulation of resistance to various therapies (Eptaminitaki
etal. 2022). Studies revealed a considerable upregulation
of lncRNA myosin light-chain kinase antisense RNA 1
(MYLK-AS1) in GBC, which was found to be connected
with a worse prognosis and clinical features. Furthermore,
induced MYLK-AS1 expression increased GBC cell prolif-
eration and invitro gemcitabine resistance. In terms of its
underlying mechanisms, MYLK-AS1 released the inhibi-
tion of enhancer of zeste 2 polycomb repressive complex
2 (EZH2) subunit expression by acting as an effective
miR-217 sponge. The upregulation of EZH2 expression
by MYLK-AS1 was found to boost cell proliferation and
resistance to gemcitabine in GBC cells. Furthermore,
EZH2 was found to directly target miR-217 (Li etal. 2021).
It was found that lncRNA ENST00000425894, known as
GBC drug resistance-associated lncRNA1 (GBCDRlnc1),
expression is elevated in GBC tissues, and it functions as a
pivotal regulator in GBC chemoresistance. The sensitivity
of established GBC cells resistant to doxorubicin (Dox)
was improved by knocking down of GBCDRlnc1, which
was achieved by blocking autophagy at an early stage in
the cell culture. This effect was observed both invitro and
invivo. According to these findings, GBCDRlnc1 may be
a potential target for therapeutic intervention in advanced
GBC (Cai etal. 2019a) (Fig.6).
It was found that the lncRNA RP11-147L13.8 was recur-
rently downregulated in GBC tumor tissues. Furthermore,
there was a correlation between a poorer prognosis and a
lower expression level of lncRNA RP11-147L13.8 in GBC
patients. In addition, research conducted both invitro and
invivo has clarified that overexpression of the lncRNA
RP11-147L13.8 prevents GBC cells from migrating and
from becoming invasive, while at the same time it increases
the cells’ vulnerability to gemcitabine. As a result, RP11-
147L13.8 can be considered a promising combination of
treatments for the management of GBC that involves the
use of gemcitabine, as it effectively suppresses the metas-
tasis of GBC chemo-resistance and metastasis through its
Fig. 6 Role of lncRNAs in drug resistance. In GBC, lncRNA MYLK-
AS1 was upregulated and associated with a worse prognosis and
clinical characteristics. Invitro gemcitabine resistance and GBC cell
proliferation enhanced with MYLK-AS1 expression. By suppressing
autophagy early in cell culture, GBCDRlnc1 knockdown increased
the sensitivity of established GBC cells resistant to doxorubicin. With
these findings, GBCDRlnc1 may be a therapeutic target for advanced
GBC. Invitro and invivo studies have shown that overexpression of
the lncRNA RP11-147L13.8 stops GBC cells from migrating and
becoming invasive while increasing their gemcitabine susceptibility.
By blocking the proteasome, SSTR5-AS1 stabilizes the RNA-bind-
ing protein NONO. SSTR5-AS1-mediated gemcitabine resistance
requires NONO.
Naunyn-Schmiedeberg's Archives of Pharmacology
modulation of the c-Jun protein phosphorylation (Zheng
etal. 2021).
It was found that GBC samples and cell lines exhibit a
substantial rise in lncRNA SSTR5-AS1, especially gemcit-
abine-resistant cell lines, showing a significant increase in
lncRNA SSTR5-AS1. A worse survival rate was associated
with increased SSTR5-AS1 expression in GBC patients. It
has been discovered that via inhibiting apoptosis, the over-
expression of SSTR5-AS1 increases resistance to gemcit-
abine. Invitro, drug-resistant GBC cells were more sensitive
to gemcitabine when SSTR5-AS1 was knocked down, and
invivo, the development of drug-resistant GBC xenografts
was significantly reduced. These results are noteworthy
because they showed that SSTR5-AS1 binds to the RNA-
binding protein NONO and stabilizes it by preventing the
proteasome from breaking down NONO. Moreover, NONO
is necessary for gemcitabine resistance mediated by SSTR5-
AS1. The information provided in this work sheds light on
the function of lncRNAs in the emergence of chemothera-
peutic resistance. Additionally, these discoveries help in
developing efficient chemotherapy methods specifically tai-
lored for patients with unresectable GBC (Xue etal. 2020).
Clinical importance oflncRNAs inGBC
Diagnosis
Early GBC is currently identified incidentally in patients
with cholelithiasis since there are no specific signs or symp-
toms linked to this disease. A palpable mass, ascites, biliary
or gastrointestinal obstruction, and weight loss are typical
signs of advanced-stage GBC (Vijayakumar etal. 2013). In
these advanced stages, most GBCs are associated with poor
prognosis, short life expectancy, and metastasis, as well as
curative treatment is not possible. The 5-year survival rate
in advanced stages (T3 and T4 stages) is less than 5%; how-
ever, if the disease was discovered earlier in its course, the
rate rises to 75%. Thus, aggressive propagation and delayed
manifestations make it one of the most catastrophic tumors
with an unfavorable outcome. The molecular markers rou-
tinely used for diagnosis of GBC lack specificity where they
are increased in some non-carcinogenic diseases. Thus,
researchers are seeking more specific and reliable diagnos-
tic methods for early detection and intervention to mitsigate
tumor progression (Vijayakumar etal. 2013, Dilek etal.
2019, Lopes Vendrami etal. 2021, Yang etal. 2022).
Diverse studies have addressed that lncRNAs could act
as innovative and exciting molecular markers for the diag-
nosis of diverse diseases (Abd-Elmawla etal. 2020, Mehana
etal. 2022, Abd-Elmawla etal. 2023, Kortam etal. 2023).
Blood plasma and urine are examples of bodily fluids where
circulatory lncRNAs have been found to function as bio-
markers for the early detection of GBC. Tumor-derived
lncRNAs usually develop a very stable secondary structure
in the peripheral circulation which is resistant to ribonu-
clease activity, rendering them appropriate molecules for
quantitative detection (Zhong etal. 2019, Niu etal. 2020).
Circulating lncRNAs function as newly developed tumor-
specific molecular markers that are employed in early cancer
diagnosis (Zhou etal. 2016, Lu etal. 2017, Xie etal. 2021b).
There are a number of pros associated with using circulating
lncRNAs as diagnostic biomarkers, including the following:
(i) compared to traditional protein-based markers, they have
a better specificity and sensitivity; (ii) they have the abil-
ity to dynamically monitor the state of the illness, includ-
ing forecasting patient survival times and the likelihood of
tumor spread and relapse; (iii) in clinical practice, lncRNAs
get clinical acceptance as noninvasive tools, high repeat-
ability, reduced patient suffering from the biopsy, and can
save patients’ costs. Statistically, the relationship between
the diagnostic test’s sensitivity and specificity is reflected in
the receiver operating characteristic curve. The diagnostic
accuracy can be measured using the computed area under
the curve (AUC). Greater AUC values signify an enhanced
diagnostic precision of the test (Mandrekar 2010, Zhou etal.
2016, Xie etal. 2021b).
In this context, Liu etal. suggested that the lncRNA
SNHG6 could be a promising marker for the diagnosis
of GBC. The gene expression of SNHG6 was elevated in
GBC and correlated with an AUC greater than 0.8 (Liu
etal. 2020d) (Table3). Furthermore, the diagnostic value
of SNHG6 has been addressed in other types of cancers such
as esophageal squamous cell carcinoma and hepatocellular
carcinoma (Birgani etal. 2018, Zhang etal. 2019). Relat-
edly, Linc00261, which was downregulated in GBC tissues
when compared to normal ones, may serve as a diagnostic
biomarker in GBC. According to Niu and his colleagues,
Linc00261 possesses high diagnostic efficiency with high
specificity and sensitivity as well as an AUC=0.8 (Niu etal.
2020). Another lncRNA is DGCR5 which was reported to
participate in GBC cell invasion, migration, and prolif-
eration. The preceding study provides the first report that
DGCR5 could be a new biomarker for the early diagnosis
of GBC (Liu etal. 2020b) (Table3). Added to that, DGCR5
was nominated as a promising biomarker in ovarian cancer
as reported by Chen etal. (2019a).
The lncRNA in GBC linked to liver metastasis (lnc-
GALM) was substantially expressed in GBC patients and
associated with low survival rates, suggesting its utility as
a diagnostic marker as reported by Li etal. (2020a). More-
over, the noticed highly expressed levels of Linc01694
in GBC suggested that it could be a potential diagnostic
marker for GBC (Liu etal. 2020a). In tandem, ANRIL and
MEG3 were closely linked with GBC development and
recommended as noninvasive biomarkers. Similarly, com-
pared with paired normal ones collected from 84 patients,
Naunyn-Schmiedeberg's Archives of Pharmacology
Table 3 Theoretical basis underlying the utility of lncRNAs as diagnostic tools in GBC
LncRNAs Expression Diagnostic/prognostic Mechanism in GBC Effect Ref
SNHG6 Up Diagnostic Targets miR-26b-5p which influences the hedge-
hog signaling pathway
Promotes EMT, proliferation, and invasion of
GBC cells
Liu etal. (2020d)
Linc00261 Down Diagnostic – Associated with GBC development and progres-
sion
Niu etal. (2020)
DGCR5 Up Diagnostic Sponges miR-3619-5p and activating MEK/
ERK1/2 and JNK/p38 MAPK pathways
Promotes proliferation, migration, invasion, and
induced apoptosis and cell cycle arrest
Liu etal. (2020b)
LncGALM Up Diagnostic/prognostic Sponges miR-200 family members, which
increase ZEB1, ZEB2, and N-cadherin.
Stimulate invasion-metastasis cascade by elevat-
ing EMT.
Li etal. (2020a), Li etal. (2020b)
Linc01694 Up Diagnostic Modulates miR-340-5p/Sox4 axis Progresses the proliferation and invasion in GBC
cells and attenuates the apoptosis
Liu etal. (2020a)
ANRIL
MEG3
Up
Low
Diagnostic/prognostic Reduces ki-67 and elevates caspase 3 levels ANRIL promotes the proliferation of gallbladder
cells and attenuates apoptosis.
MEG3 mitigates cell proliferation and promotes
apoptosis.
Xie etal. (2021a)
CCAT1 Up Diagnostic/prognostic Sponges miRNA-218-5p which stimulates Bmi1
gene expression
Promotes proliferation and invasiveness. Ma etal. (2015a), Ma etal. (2015b)
FOXD2-AS1 Up Diagnostic Stimulates MLH1 methylation by recruiting
DNMT1 to the MLH1 promoter, thus mitigat-
ing MLH1 transcription.
Stimulates cell proliferation, invasion, and
migration, whereas reduces cell apoptosis
Gao etal. (2021a)
GBCDRlnc1 Up Diagnostic Interacts with phosphoglycerate kinase 1 and
downregulates autophagy initiator ATG5-
ATG12 conjugate.
Enhances autophagy at the initial stage,
decreases the sensitivity of Dox-resistant in
GBC
Cai etal. (2019b)
HGBC Up Diagnostic/prognostic Sponges miR-502-3p and inhibit SET gene
expression
Acts via a positive regulatory loop consisting of
HEGBC, IL-11, and STAT3.
Stimulates cell proliferation and invasion invitro
and in xenografted tumors.
Hu etal. (2019a), Yang etal. (2018)
DILC Up Diagnostic Influences Wnt/β-catenin axis. Promotes the self-renewal, tumorigenicity, pro-
liferation, and metastasis
Liang etal. (2019)
LncROR Up Diagnostic Promotes EMT phenotype driven by TGF-β1 Activates the tumor cells proliferation, migra-
tion, and invasion
Wang etal. (2016d)
LncEPIC1 Up Diagnostic Represses lncRNA LET expression. Stimulates proliferation and inhibits apoptosis Liu etal. (2016b)
FIRRE Up Diagnostic Sponge miR-520a-3p via controlling YOD1 gene
expression
Stimulates proliferation and migration, and
inhibits apoptosis
Wang etal. (2021)
SPRY4-IT1 Up Diagnostic – Enhances GBC cell proliferation Yang etal. (2017)
PVT1 Up Diagnostic PVT1 recruited DNMT1 via EZH2 to the miR-
18b-5p DNA promoter and suppressed the
transcription of miR-18b-5p through DNA
methylation.
Enhances GBC cell proliferation invitro and
invivo.
Jin etal. (2020b)
LncLET Down Diagnostic Promotes cell cycle arrest at G0/G1 phase and
the induction of apoptosis under hypoxic
conditions
Mitigates the invasion of GBC under hypoxic or
normoxic conditions invitro.
Ma etal. (2015d)
Naunyn-Schmiedeberg's Archives of Pharmacology
the level of ANRIL was highly upregulated and the level
of MEG3 was downregulated in GBC tissues (Liu etal.
2016a). The lncRNA CCAT1 was elevated in the tissues
of 40 patients with GBC in comparison to adjacent normal
tissues (Ma etal. 2015a). Gao etal. (2021a) reported that
the lncRNA FOXD2-AS1 was highly upregulated in GBC
tissues in comparison with the adjacent normal tissues.
Furthermore, a newly identified lncRNA is GBCDRlnc1
which was highly expressed in GBC tissues (Cai etal.
2019b). All of these aberrated lncRNAs may help to diag-
nose and treat GBC early.
The lncRNA which is referred to as highly expressed in
GBC (HGBC) was markedly elevated in GBC tissues than
adjacent benign tissues as reported by Hu and his colleagues
(2019a). Relevantly, the lncRNA DILC was highly expressed
in both GBC stem cells and patients’s tissues reflecting its
plausible role as a diagnostic molecule (Liang etal. 2019).
The lncRNA ROR which has been reported in several types
of malignancies, was also elevated in GBC and stimulated
the EMT in GBC (Wang etal. 2016d). FU etal. submitted
that the lncRNA EPIC1 which is named as epigenetically
induced lncRNA1 was highly differentiated in GBC giving a
theoretical basis for their utility in diagnosis (Fu etal. 2021).
In the same milieu, Wang etal. reports that the lncRNA
FIRRE which is referred to as a functional intergenic repeat-
ing RNA element could participate in the diagnostic strategy
of GBC. This may be attributed to its high expression pat-
tern in GBC and its close association with stimulated pro-
liferation and cancer invasion (Wang etal. 2021) (Table3).
Moreover, the lncRNAs SPRY4-IT1 and PVT1 exerted their
oncogenic role in GBC development suggesting its promis-
ing clinical marker tool (Yang etal. 2017, Jin etal. 2020b).
Another lncRNA is HOXA cluster antisense RNA2 (HOXA-
AS2) which was overexpressed in GBC tissues (Zhang etal.
2017b). On the opposite, Ma etal. (2015d) found that the
tumor suppressor lncRNA LET could be valuable in the
diagnosis of GBC where it was downregulated in GBC
in comparison to paracancerous normal tissues. Wu etal.
(2017) introduced the lncRNA PAGBC, which is referred to
as prognosis‐associated GBC lncRNA as a diagnostic tool
in GBC based on its role in stimulating tumor growth and
metastasis.
Indeed, several differentially expressed lncRNAs were
identified in GBC that contribute to GBC development.
However, their clinical utility as diagnostic markers need
further investigations to fully interpret the molecular mecha-
nisms of GBC. Additionally, the mechanisms behind their
secretion and transport to the circulation should be reported
precisely to put forward their utility as plasma or serum
noninvasive diagnostic biomarkers. Quantitative real-time
PCR is regarded as the gold standard for lncRNA determi-
nation approaches. However, there are no unified standard
extraction techniques, endogenous controls, or quantification
Table 3 (continued)
LncRNAs Expression Diagnostic/prognostic Mechanism in GBC Effect Ref
PAGBC Up Diagnostic Sponges miR‐133b and miR‐511.
Stimulates AKT/mTOR
Promotes tumor growth and metastasis. Wu etal. (2017)
AFAP1-AS1 Up Prognostic – Proliferation, invasion, epithelial-mesenchymal
transition
Yang etal. (2017)
HOTAIR Up Prognostic Enhances the expression of c-Myc via sponging
miR-130a
Migration, proliferation Ma etal. (2014)
H19 Up Prognostic Acts via the H19/miR-342-3p/FOXM1 and H19/
miR-194-5p/AKT2 axis.
Proliferation, tumorigenicity, migration, inva-
sion, epithelial-mesenchymal transition
Wang etal., (2016f), Wang etal. (2022)
MALAT1 Up Prognostic MiR-363-3p’s competing endogenous RNA,
MALAT1, controls the expression of MCL-1.
Proliferation tumorigenicity, migration, invasion,
metastasis
Wu etal. (2014a), Wang etal. (2016g)
MINCR Up Prognostic Alters miR-26a-5p’s capacity to bind to EZH2 Proliferation, migration, tumorigenicity, inva-
sion, epithelial-mesenchymal transition
Wang etal. (2016g)
OIP5-AS1 Up Prognostic Reduces the expression of miR-143-3p Proliferation, migration, invasion Li etal. (2020b)
SSTR5-AS1 Up Prognostic NONO/SSTR5_AS1 interaction stops NONO
from degrading
Drug resistance Xue etal. (2020)
MEG3 Up Prognostic – Inhibit poor prognosis, inhibit proliferation,
inhibit migration, inhibit metastasis
Liu etal. (2016b), Jin etal. (2018), Bao
etal. (2020)
Naunyn-Schmiedeberg's Archives of Pharmacology
techniques (Yang etal. 2014, Bhan etal. 2017, Jiang etal.
2019).
Thereby, to introduce all of these circulating lncRNAs
into the clinical realm, additional points should be taken
into consideration such as the type and volume of sample
needed, the used anticoagulant, and the stored temperature.
The extraction techniques and endogenous regulation of
lncRNAs in bodily fluids ought to be uniform. Providing
standard techniques for evaluating the quality of lncRNA
and the accuracy of qPCR data should be more precise and
reliable in early diagnosis of GBC. Finally, a larger pool of
prospective patients is warranted to assess the performance
of these diagnostic tools in terms of sensitivity, specificity,
and diagnostic efficiency (Shi etal. 2016).
Prognosis
LncRNAs are increasingly being recognized as possible
biomarkers for disease development, metastasis, and patient
prognosis. In this discussion, we explore the function of
many lncRNAs as indicators for diagnosis and prognosis in
GBC. AFAP1-AS1, a lncRNA, is highly expressed in GBC
tissues and is linked to larger tumor growth and an unfavora-
ble prognosis in cancer patients (Li etal. 2019c). AFAP1-
AS1 knockdown may inhibit proliferation and invasion. Zhu
etal. found that the ceRNA AFAP1-AS1, which is overex-
pressed in GBC tissues and cell lines, controls the hsa-miR-
15a-5p/bcl-2 axis and promotes the growth and metastasis of
GBC cells. Zhu etal. found that AFAP1-AS1 overexpressed
in GBC tissues and cell lines is a ceRNA of hsa-miR-15a-5p,
which regulates the hsa-miR-15a-5p/bcl-2 axis and drives
GBC cell proliferation and metastasis. This may help treat
GBC clinically (Zhu etal. 2022). Also, ANRIL is upregu-
lated in GBC tissues and increases proliferation and tumor
size in a murine model, indicating its involvement in cancer
progression (Li etal. 2019c) (Table3).
CCAT1 is another lncRNA found in various cancers, such
as colorectal and gastric cancer (Liu etal. 2019). Gastric
and colorectal cancer tissues have increased expression of
it, particularly in advanced stages and lymph node metasta-
ses. The expression of CCAT1 is correlated with advanced
tumor node metastatic stage, invasion of lymph nodes, and
tumor status, indicating a poor prognosis for colorectal
and stomach cancer. Knocking down CCAT1 invitro and
invivo reduces the occurrence of S-phase, invasion, and the
growth of tumors. An RNA molecule of significant length,
GALM expression is elevated in tumor tissues from glio-
blastoma (GBM) and is linked to lymph node metastases,
poorly differentiated cells, and an advanced TNM stage. The
expression of GALM is associated with decreased survival
in GBC, suggesting a worse prognosis. The GALM gene
was artificially increased in GBC cell lines to investigate its
role, revealing enhanced migratory and invasive capabilities.
The invivo experiments showed that GALM enhanced the
liver metastatic capacity, indicating its potential to enhance
EMT and metastasis in GBC. GALM interacts with miR-200
family members and IL-1β mRNA, functioning as molecular
decoys (Hu etal. 2019b).
HEGBC, a lncRNA, rises substantially in GBC cell
lines and tissues and is highly associated with lymph node
metastases and TNM stages. High HEGBC expression in
GBC patients is related to poor survival. Ectopic HEGBC
expression increases proliferation and migration, reducing
apoptosis. HEGBC overexpression in GBC cell lines in
nude mice enhances tumor growth, proliferation markers,
and liver metastasis. By binding to the promoter, HEGBC
promotes IL-11 transcription and activates STAT3 signal-
ing pathway cells. GBC tissues overexpress malignancy-
promoting lncRNA HOTAIR. Ma etal. analyzed HOTAIR
expression in 65 GBC tissue samples to determine its role.
In tumor tissues, HOTAIR expression was much greater than
in matching normal tissues. It may be a GBC progression
and prognosis marker since gallbladder tumors express it
more and disseminate it to regional lymph nodes. HOTAIR
increases GBC cell line proliferation and migration, corre-
lates positively with c-Myc expression, and negatively with
miRNA-130a, suggesting a role in GBC progression (Ma
etal. 2014).
It has been demonstrated that LncRNA H19, which is
expressed in a variety of malignancies, contributes to the
acquisition of different oncogenic characteristics (Ghafouri-
Fard etal. 2020). Patients with GBC had worse survival
rates and larger tumors due to the higher expression of H19
in malignant cells compared to non-cancerous gallbladder
tissue. The expression of the AKT2 gene and protein is
increased by H19, whereas the expression of miR-194-5p is
decreased. The modulation of the H19/miR-194-5p/AKT2
axis may contribute to the oncogenic properties of H19 in
GBC by influencing cell proliferation and EMT (Wang etal.
2016e, Wang etal. 2016f, Wang etal. 2022). Thus, treating
GBC in humans, H19 may therefore be regarded as a pos-
sible prognostic biomarker and/or therapeutic target.
Metastasis-associated lung adenocarcinoma transcript
1 (MALAT1) is a lncRNA that promotes the growth of
cancerous tumors and influences the process of alternative
splicing of pre-messenger RNA (Zhang etal. 1993). Interac-
tion with unmethylated CBX4 controls gene translocation
between the polycomb complex and interchromatin bodies.
Silencing MALAT1 reduces GBC cell growth but enhances
the G2/M cell cycle transition. MALAT1 inhibition reduces
tumor and xenograft growth invivo. MALAT1 knockdown
stops GBC cell invasion. MALAT1 is a downstream tar-
get of MMP9. MALAT1 deletion activates ERK/MAPK by
decreasing MMP9. These findings support MALAT1 as a
GBC therapeutic and prognostic marker (Wu etal. 2014a,
Wang etal. 2016g).
Naunyn-Schmiedeberg's Archives of Pharmacology
The expression of lncRNA MINCR is elevated in glio-
blastoma (GBM) tissues and is correlated with larger tumor
size, lymph node metastases, and a shorter overall survival
time. These findings indicate that MINCR is linked to a poor
prognosis in GBM patients. Knocking down MINCR leads
to a decrease in cell proliferation, migration, invasion, and
EMT under laboratory conditions. Tumor volume decreased
in mice that were injected with GBC si-MINCR cells.
MINCR might potentially influence the binding of miR-
26a-5p to EZH2 by interacting with miRNA ribonucleo-
protein complexes. NEAT1, a different lncRNA, is highly
expressed in GBC tissues and might potentially be down-
regulated to decrease the formation of colonies, migration,
invasion, and tumor growth (Wang etal. 2016g). LncRNA
OIP5-AS1 is a new lncRNA that plays a role in cancer devel-
opment (Wang etal. 2020b). It has been overexpressed in
GBC cell lines and is linked to proliferation, migration, and
invasion (Li etal. 2020b). PVT1 is an additional lncRNA
that its expression is increased in GBC tissues. It is linked
to a more advanced TNM stage, a distant spread of cancer,
and a poorer overall survival rate. PVT1 serves as a powerful
and autonomous prognostic marker for patients with GBC,
indicating an unfavorable prognosis. Suppression of PVT1
hampers cellular growth, the formation of colonies, move-
ment, and infiltration, indicating its potential to control EMT
and the advancement of cancer. The observed effects are
likely caused by the increased expression of HK2, which is
mediated by PVT1 through its ability to competitively bind
to miR-143, a kind of endogenous RNA (Chen etal. 2019b,
Jin etal. 2020a, Liu and Xu 2020).
Gemcitabine-resistant GBC cell lines express SSTR5-
AS1, a lncRNA involved in chemotherapy. Increased
SSTR5-AS1 expression reduces programmed cell death,
indicating drug resistance. It is also expressed at higher
levels in GBC tissues and cell lines and is associated with
worse survival. SSTR5-AS1 may predict GBC prognosis
(Yang etal. 2017). The expression of lncRNA-LET inde-
pendently predicts the metastasis and mortality of GBC
patients. Hypoxia facilitates the proliferation of tumors,
enhances their malignant properties, and contributes to their
resistance to treatment. Hypoxia decreases the expression of
lncRNA-LET in GBC EZ-GB2 and SGC-996 cells. When
GBC cells are exposed to low oxygen levels (hypoxia), the
overexpression of lncRNA-LET leads to an increase in the
levels of p21, Caspase-3, and the Bax/Bcl-2 ratio. These
findings indicate that lncRNA-LET plays a role in promot-
ing apoptosis (Ma etal. 2015a, Shen etal. 2015, Yan etal.
2017). The lncRNA-MEG3 is expressed at lower levels in
glioblastoma (GBM) tissues than in normal tissues, which is
associated with a worse prognosis and the spread of cancer
cells to the lymph nodes. MEG3 overexpression suppresses
cell growth, inhibits colony formation, and triggers apoptosis
in GBM cell lines. In an invivo setting, the overexpression
of a certain gene leads to a reduction in the formation of
tumors and a decrease in the presence of the Ki-67 marker in
the BALB/c nude mouse model. MEG3 suppresses the inva-
sion of NOZ cells and facilitates the degradation of EZH2 by
ubiquitination. This process regulates the LATS2 and NF-κb
pathways (Liu etal. 2016b, Jin etal. 2018, Bao etal. 2020).
Comparably, GCASPC is a noncoding RNA that is down-
expressed in GBC tissues and has been linked to decreased
overall survival (OS), disease-free survival (DFS) rates,
advanced disease stage, and tumor size (Ludwig etal. 2016).
Future prospective andconclusions
LncRNAs play a pivotal role in the control of gene expres-
sion at different levels, such as chromatin modification, tran-
scription, and post-transcriptional processing. Furthermore,
they have been identified to possess oncogenic and tumor-
suppressive functions. One of the most active areas in sci-
entific research is the use of lncRNAs for clinical practice.
GBC is an uncommon disease that has a poor prognosis.
It is characterized by a particular geographic distribution
and a distinct set of risk factors. Regretfully, there are few
treatment options available for GBC. Radiation, surgery,
and cytotoxic chemotherapy are among the limited sur-
vival benefits of GBC treatments. It is essential to under-
stand the molecular pathophysiology of GBC to advance
designed treatment strategies. Early diagnosis and prediction
of potential metastasis are key points for improving GBC
patient outcomes. For this purpose, diagnostic and prognos-
tic biomarkers are needed for the proper selection of the
best treatment option for preoperative and/or postoperative
GBC cases. The most important advantage of lncRNAs is
their presence in body fluids, making it possible to use them
as non-invasive biomarkers in clinics. So, more studies on
circulating lncRNAs should be performed for the identifica-
tion of lncRNAs that may be used practically as non-invasive
biomarkers for GBC. The low expression levels of several
lncRNAs present a challenge in this regard, necessitating the
use of procedures based on amplification and/or enrichment
of the circulating molecules. It is important to note that there
were no reliable internal controls for lncRNA in serum or
blood. In order to precisely estimate the circulating lncRNA
levels in the future, stable and reliable internal controls are
required. Overall, elucidating the mechanism of lncRNAs’
aberrant expression and the downstream mechanism of lncR-
NAs in malignancies will help us better understand lncRNA
expression and will enable us to develop new tumor markers
for clinical diagnosis and prognosis evaluation of tumors.
In conclusion, lncRNAs have critical roles in GBC initia-
tion, progression, and metastasis through controlling various
cellular processes such as proliferation, apoptosis, angiogen-
esis, and EMT. In particular, SNHG6, Linc00261, GALM,
Naunyn-Schmiedeberg's Archives of Pharmacology
OIP5-AS1, MINCR, DGCR5, MEG3, TUG1, and DILC
are key players in regulating the aforementioned processes.
Dysregulation of lncRNAs in GBC can be observed in both
bodily fluids and tissues, offering the potential for identify-
ing innovative non-invasive biomarkers for diagnosing, pre-
dicting outcomes, and treating GBC. These markers could
eventually find clinical applications in the future.
Acknowledgements The authors are thankful to the Deanship of Grad-
uate Studies and Scientific Research at University of Bisha for sup-
porting this work through the Fast-Track Research Support Program.
The authors would like to thank the Deanship of Scientific Research at
Shaqra University for supporting this work.
Authors contributions Conception and design: H.E., O.A.M., R.M.,
M.B.Z., and A.S.D. Collection and/or assembly of the data: A.F.R.,
Mu.A.A., and N.E. Manuscript writing: N.A.A.A., A.H., Ma.A.A., and
A.M.E. All the authors have read and approved the published version
of the manuscript.The authors confirm that no paper mill and artificial
intelligence was used.
Data availability Not applicable.
Declarations
Ethical approval Not applicable.
Consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests The authors declare no competing interests.
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