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International Journal of Biological Macromolecules 222 (2022) 1151–1167
Available online 1 October 2022
0141-8130/© 2022 Published by Elsevier B.V.
Review
Non-coding RNAs targeting notch signaling pathway in cancer: From
proliferation to cancer therapy resistance
Mehrdad Hashemi
a
,
b
, Sahar Hasani
b
, Shima Hajimazdarany
b
,
c
, Seyed Reza Mirmazloomi
b
,
Sara Makvandy
d
, Abbas Zabihi
e
, Yeganeh Goldoost
b
, Nazanin Gholinia
b
,
Amirabbas Kakavand
b
, Alireza Tavakolpournegari
f
, Shokooh Salimimoghadam
g
,
*
,
Noushin Nabavi
h
, Ali Zarrabi
i
, Afshin Taheriazam
b
,
j
,
**
, Maliheh Entezari
a
,
b
,
***
,
Kiavash Hushmandi
k
,
*
a
Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
b
Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
c
Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
d
Department of Biology, Zarghan Branch, Islamic Azad University, Zarghan, Iran
e
Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Hamedan Branch, Hamedan, Iran
f
Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Aut`
onoma de Barcelona, Cerdanyola del Vall`
es, 08193 Barcelona,
Spain
g
Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
h
Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6 Vancouver, BC, Canada
i
Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
j
Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
k
Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
ARTICLE INFO
Keywords:
Cancer
Notch
miRNA
lncRNA
Cancer therapy
ABSTRACT
Cancer is a challenging to treat disease with a high mortality rate worldwide, nevertheless advances in science
has led to a decrease in the number of death cases caused by cancer. Aberrant expression of genes occurs during
tumorigenesis therefore targeting the signaling pathways that regulate these genes' expression is of importance in
cancer therapy. Notch is one of the signaling pathways having interactions with other vital cell signaling mol-
ecules responsible for cellular functions such as proliferation, apoptosis, invasion, metastasis, epithelial-to-
mesenchymal transition (EMT), angiogenesis, and immune evasion. Furthermore, the Notch pathway is
involved in response to chemo- and radiotherapy. Thus, targeting the Notch signaling pathway in cancer therapy
can be benecial for overcoming the therapeutic gaps. Non-coding RNAs (ncRNAs) are a class of RNAs that
include short ncRNAs (such as micro RNAs) and long ncRNAs (lncRNAs). MicroRNAs (miRNAs) are ~22 nu-
cleotides in length while lncRNAs have more than 200 nucleotides. Both miRNAs and lncRNAs control vital
cellular mechanisms in cells and affect various signaling pathways and Notch is among them. The current review
aims to discuss the critical role of ncRNAs in the regulation of the Notch signaling pathway by focusing on
different cancer hallmarks including proliferation, apoptosis, autophagy, EMT, invasion, metastasis, and resis-
tance to therapies.
* Corresponding authors.
** Correspondence to: A. Taheriazam, Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
*** Correspondence to: M. Entezari, Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University,
Tehran, Iran.
E-mail addresses: Shokoohmoghadam@yahoo.com (S. Salimimoghadam), a.taheriazam@iautmu.ac.ir (A. Taheriazam), mentezari@iautmu.ac.ir (M. Entezari),
Kiavash.hushmandi@gmail.com (K. Hushmandi).
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules
journal homepage: www.elsevier.com/locate/ijbiomac
https://doi.org/10.1016/j.ijbiomac.2022.09.203
Received 3 September 2022; Accepted 22 September 2022
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1152
1. Introduction
As the most life-threatening disease, cancer is one of the main causes
of death worldwide. In the United States, almost 2 million new cancer
cases were recognized and the number of patients who die from cancer is
estimated to be more than 600,000 in 2022 [1]. Common causes of
death from cancer are local recurrence and distant metastasis [2]. Many
cancers have an invasive nature and among them, lung, breast, prostate,
and gastrointestinal cancers have devoted the most mortality rate to
themselves. Thanks to the past and current progress against cancer,
early-stage detection, targeted therapies, and aggressive techniques like
surgeries have brought cancer treatment under control, but it remains
the most difcult-to-treat disease yet [1].
During tumorigenesis, normal cells are converted to tumor cells and
genes have a signicant role in this process. Tumor cells are known by
certain characteristics called cancer hallmarks that include sustained
proliferation, growth suppressors' dysfunction, metabolic reprogram-
ming, resistance to apoptosis, angiogenesis promotion, invasion, and
metastasis [3]. Increasing evidence suggests that tumorigenesis is highly
regulated by cellular signaling pathways. One of the fascinating
signaling pathways is Notch which is broadly involved in cancer biology
and attracts notable attention for designing Notch-targeting therapies
for cancer as a promising tool [4]. Notch is a highly carcinogenic
pathway that regulates various cancer hallmarks and plays a critical role
in cancer cell proliferation, apoptosis inhibition, and cell fate. Thus, it
could be a valuable diagnostic and therapeutic target in cancer [5].
Recent insights have linked non-coding RNAs (ncRNAs) to cancer
biology, therapy, and resistance to conventional therapies [6,7]. More
than a fth of the human genome is transcribed to RNA during different
conditions. However, only 2 % of these transcriptomes can be translated
into proteins. The vast part of the remaining untranslated transcriptome
includes a notable number of ncRNAs. ncRNAs are the dominant form of
RNA. More than 95 % of them are classied by their length; short non-
coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) which
have less and more than 200 nucleotides, respectively. ncRNAs tightly
regulate cellular function by targeting gene expression, protein trans-
lation, and reorganizing the genome. Moreover, ncRNAs have been
explored extensively in cancer progression for their roles in carcino-
genesis or tumor suppression [8–11].
This review details the regulation of Notch signaling by ncRNAs in
different cancers by focusing on cancer hallmarks including prolifera-
tion, cell survival, invasion, and metastasis. Moreover, ncRNAs' role in
cancer therapy and resistance through targeting Notch pathways is
discussed.
2. Non-coding RNAs
The most well-studied part of the genome belongs to protein-coding
genes. However, this proportion accounts for 2 % of the genome. The
other large remaining sequences of the genome are related to non-
protein coding genes which are responsible for physiological and
developmental functions. These functions are particularly apparent for a
class of ncRNAs called microRNAs (miRNAs). During the past two de-
cades, it has become gradually evident that genetic and epigenetic al-
terations in the miRNAs genome can be considered as disease hallmarks
[12,13]. ncRNAs are divided into two main classes based on their length:
small non-coding RNAs (sncRNAs) with no more than 200 nucleotides,
and long non-coding RNAs with greater than 200 nucleotides. Despite
this classication, lncRNAs have similarities to miRNAs. For example,
both of them are transcribed by RNA polymerase II. An explosion of
studies for sncRNAs suggests that they represent a diverse group and
come in a variety of molecules with different sizes and functions,
including tumor suppressors and oncogenic molecules. miRNA, piwi-
interacting RNA (piRNA), small interfering RNA (siRNA), and transfer
RNA-derived small RNAs (tsRNAs) are among very known sncRNAs
[14,15].
As master regulators, miRNAs control the expression of a vast
number of genes at different levels. Among sncRNAs, miRNAs are widely
studied in cancer biology and therapy. MiRNAs exert their function in
cancer in a tumor suppressor or tumor-promoting manner. Interestingly,
some miRNAs have a dual role of either tumor promoter or suppressor
depending on cellular context [15]. For example, miRNA-29 has
different expression levels in indolent and aggressive types of B-cell
chronic lymphocytic leukemia [16].
RNA polymerase II (Pol II) is responsible for the transcription of
miRNAs that produce pri-miRNAs with at least one hairpin region as the
substrate for Microprocessors. Microprocessors are complexes
comprising of Drosha, RNase III enzyme, and RNA-binding protein Di
George Syndrome Critical Region Gene 8 (DGCR8). After binding of
Microprocessors, Drosha cleaves pri-miRNA to produce the precursor
miRNA (pre-miRNA) with ~60 nucleotides. Once formed, pre-miRNAs
translocate into the cytoplasm by the action of Exportin 5 and Ran-
GTP complex. After being processed by the RNase III enzyme Dicer, a
miRNA duplex is generated by the function of Dicer. Then, the formed
miRNA duplex is loaded into an Argonaute protein, leading to the pro-
duction of a complex named RNA-induced silencing complex (RISC)
which contains the mature miRNA of ~22 nucleotides [17,18]. MiRNAs
regulate their targets at the post-transcriptional level by binding to the 3′
untranslated region (3′UTR) of their messenger RNA (mRNA). This
interaction leads to degradation of the mRNA or translational inhibition
of functional proteins [19].
A very newly discovered class of sncRNAs is tsRNAs which are also
named tRNA-derived stress-induced RNAs (tiRNAs) and tRNA fragments
(tRFs). Although tsRNAs have not been extensively studied yet, their
role in cancer is shown. They have a wide range of targets including
Argonaute and Piwi proteins which include miRNAs and piRNAs,
respectively [20]. These sncRNAs are derived from tRNA. tRNAs are
transcribed by RNA polymerase III (RNA Pol III) to produce pre-tRNA.
Then, 5′and 3′ends are removed by RNase P and Z, and tRNA nucleo-
tide transferase adds a CCA sequence to the 3′end. The mature tRNA has
four loops including (1) D-loop, (2) anticodon loop, (3) variable loop,
and (4) pseudouracil loop (T
ψ
C loop). TsRNAs are derived from
different parts of tRNA using Dicers and/or Angiogenin. For example,
tRF-5, tRF-3, and tiRNA are derived from D-loop, T
ψ
C loop, and anti-
codon loop respectively [21]. tsRNA functions are include RNA
silencing, RNA stability, regulation of RNA reverse transcription, and
regulating protein translation. Moreover, a body of studies has illumi-
nated the role of tsRNAs in different cancers [21,22].
CircRNAs, as a class of long ncRNAs, are single-strand RNA mole-
cules without 5′caps and 3′tails which are generated from pre-mRNAs
transcripts during the process of back-splicing [23] or through lariat-
driven circularization. Back-splicing is mediated by cis-acting and
trans-acting factors. CircRNAs are grouped based on their site of origin:
exonic circRNAs, circular intronic RNAs, and exon-intron circRNAs
[24–27]. They have different functions in the cells including miRNA
regulation, regulating translation, RNA maturation, protein localization,
role as decoys, and scaffolding. Besides, circRNA's roles in the regulation
of human disorders such as cancer have been studied. These studies
suggest that circRNAs are involved in drug resistance and oncogenesis
and can be used as promising diagnostic and prognostic biomarkers
[28–33].
H19 and XIST were the rst discovered and studied lncRNAs during
studies of embryonic development and inactivation of the X chromo-
some [15,34,35]. With a length of more than 200 nucleotides, lncRNAs
are transcribed by RNA Pol II. LncRNAs genomic region is enriched with
histone H3 trimethylation at Lys36 (H3K36) through the body of related
genes and histone H3 Lys4 trimethylated (H3K4) at the start site of
transcription. Being spliced through canonical pathways, matured
lncRNAs have their 5′ends capped by 7-methyl guanosine with a pol-
yadenylated 3′tail [36–39]. Based on the site of lncRNAs function, they
can be divided into two groups: lncRNAs that function in cis (exert local
effects close to their transcription site) or trans (exert their effects on
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1153
distant cellular or genomic regions). X-inactive specic transcript (XIST)
and HOX antisense intergenic RNA (HOTAIR) are two well-known
lncRNAs that exert their functions in cis and trans regions, respectively
[40]. LncRNAs have a myriad of functional roles in cells and affect
different genes and factors to regulate their function. For example,
lncRNAs modulate the pre-mRNA splicing process to regulate mRNA.
Moreover, they regulate the translation, and repression process medi-
ated by miRNAs, act as scaffolds, increasing genetic diversity, and play
roles in cellular signaling pathways (Fig. 1) [41].
3. Notch signaling pathway
Notch receptor gene which encodes a large transmembrane receptor
of Type I was rst studied in 1985 [42]. The notch pathway is one of the
highly conserved signaling pathways involved in creating diversity be-
tween various species and different cell types. The notch signaling
pathway has a critical role in regulating cellular processes including cell
growth, cell death, and differentiation to promote or suppress them in a
context-dependent manner. Regarding its extensive role in a high range
of cell processes and different tissues, dysregulation of Notch is linked to
various cellular dysfunctions and human disorders, cancer being among
them [43].
After being produced in the endoplasmic reticulum, Notch co-
operates with an O-fucosyl transferase (O-Fut) and is translocated into
the cytoplasm to be processed in the Golgi apparatus using an enzyme
named Furin-like convertase. Next, Notch is glycosylated by O-Fut and
glycosyltransferase factors like Fringe and is transported to the cell
membrane. By binding to its ligands, the Notch pathway is activated.
Notch ligands are proteins located on the cell membrane including an N-
terminal domain called DSL (Delta, Serrate, and LAG-2) with extracel-
lular domains that are contained repeats of epidermal growth factor
(EGF). Ligands are classied according to the absence or existence of
cysteine-rich (CR) areas into two groups: Delta or Delta-like (DLL1/3/4),
and Jagged (Jagged1/2). Notch receptor has three parts of extracellular,
transmembrane, and intracellular domains. The extracellular domain is
characterized by EGF repeats, CR LIN repeats, and the linker region that
links the extracellular part to the other parts. The intracellular domain
contains, an RBP-J association molecule (RAM), ankyrin repeats (Ank),
and a C-terminal PEST domain. Moreover, different Notch receptors may
have various protein-protein interaction motifs [44–46].
Notch signaling can be activated when a ligand binds to the Notch
receptor. An appropriate ligand should effectively induce receptor
Fig. 1. Biogenesis of non-coding RNAs.
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1154
proteolysis which results in releasing an active fragment of Notch from
the membrane tether, called Notch intracellular domain (NICD). Re-
ceptor proteolysis is mediated by ADAM10 or TACE (TNF-a-converting
enzyme) metalloprotease which paves the way for the function of the
γ-secretase complex to mediate a second cleavage. The produced NICD is
translocated into the nucleus to associate with a ubiquitous DNA binding
protein named CSL (CBF1/suppressor of Hairless/LaG1), the co-
activator Mastermind (Mam), Ski-interacting protein (SKIP), and other
transcription factors to mediate a transcriptional complex and regulate
downstream genes. A co-repressor (Co-R) complex that inhibits target
gene transcription is released after NICD binding to its targets. For
activation and elongation of transcription of target genes, Histone ace-
tyltransferases (HATs; including p300 and PCAF/GCN5) and chromatin-
remodeling complexes (including Dom, BRM, and TRA1/TRRAP) are
recruited. Then, cyclin-dependent kinase-8 (CDK8) and SEL10 ligase
modify NICD to make it suitable for the function of the proteasome to be
degraded. By degradation of NICD, Co-R complexes are binding to CSL
again until re-initiating the cycle by NICD (Fig. 2) [43–45,47].
In addition to the canonical pathways, there is a non-canonical
pathway for activation of Notch signaling, in which Notch interacts
with other transcription factors rather than CSL, such as NF-κB, β-cat-
enin, and HIF-1
α
[46]. In non-canonical Notch signaling, Notch is acti-
vated by a non-canonical ligand or is activated without ligands.
Moreover, some forms of non-canonical activation of Notch do not
require the cleavage of Notch receptor. In another form, other nuclear or
cytoplasmic factors are recruited instead of CSL protein [48]. One of the
examples of the non-canonical pathway of Notch is the association be-
tween IKKa and Notch1 to mediate an NF-kB dependent transcription
which is active in cervical cancer [49].
There are four types of Notch receptors including Notch1 to 4.
Notch3 and 4 are shorter in their extracellular domain than Notch1 and
2. Moreover, they don't have the intracellular transcriptional activating
domain. Among these four Notch receptors, Notch4 is the only receptor
that lacks the cytokine response region [50]. Initially, the function of the
Notch pathway in cancer was dened through a study of chromosomal
translocation in T-cell lymphoblastic leukemia. Studies have shown that
a Drosophila Notch-like gene exists in the human genome and its rear-
ranged form may be involved in tumor pathogenesis [51]. After
Fig. 2. Notch signaling pathway activation, function, and degradation.
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1155
identifying the Notch pathway as an oncogenic factor, a large number of
studies target this signaling pathway as a therapeutic approach such as
γ-secretase suppressors and monoclonal antibodies that target Notch
ligands or receptors, leading to Notch inhibition [48]. Designing a so-
phisticated approach for Notch-based cancer therapy requires more
complex and precise investigations of this signaling pathway [45]. The
outcomes of the Notch pathway are controlled by various types of reg-
ulations. For example, the expression pattern of receptors, ligands, and
modifying enzymes is one of the common strategies in their regulation.
Interestingly, a cis-inhibition mechanism exerted by ligands and re-
ceptors of the same cells could regulate this pathway [52].
Notch receptors are involved in a different types of cancers by
regulating vital cellular processes such as apoptosis, drug resistance,
invasion, epithelial-mesenchymal transition (EMT), metastasis, and
promoting tumor vasculature [45] (Table 1). The data in the
Table provided indicates that the Notch function is context-dependent
and is an oncogene or tumor suppressor based on the cancer type or
even a different cancer cell line of the same cancer type.
4. Regulation of Notch signaling pathway by miRNAs in cancer
4.1. Cancer progression
Accumulating research conrms the critical function of the Notch
signaling pathway in cancer cell proliferation [98–103]. It is now known
that miRNAs and Notch signaling either work together or in opposite
ways to shape cellular activities. Understanding the molecular cues and
mechanisms between miRNAs and Notch signaling and their impact on
cancer biology can pave the way for the development of promising
therapeutic strategies. Here, we provide the current knowledge
regarding the interaction between miRNAs and Notch signaling pathway
in the context of different cancers. As mentioned previously, miRNAs
can display either oncogenic or tumor suppressor functions. MiRNA-34
is a tumor suppressor miRNA with a decreased expression in ovarian
cancer. MiRNA-34 is capable of inducing tumor cell apoptosis and
autophagy to decrease tumor cell proliferation and in this case, miRNA-
34 increases the expression level of Bax, as an apoptosis-associated
factor, and LC3 II/p62 as an autophagy-related protein. In one study,
it was shown that miRNA-34 induces ovarian cancer cell death by tar-
geting Notch1 and suppressing it [104]. In contrast, miRNA-223 is a
tumor-promoting agent which positively affects Notch signaling
pathway in colorectal cancer. For this, miRNA-223 inhibits FBXW7 to
increase tumor cell proliferation. FBXW7, in turn, is a tumor suppressor
factor with critical roles in cancer including the regulation of prolifer-
ation, differentiation, and cell division. Reversely affecting FBXW7,
miRNA-223 binds to the 3′UTR region of FBXW7 and decreases its
expression levels to increase Notch signaling function. Ultimately, the
Notch pathway increases tumor cell proliferation [105].
Various other target genes have been identied to affect Notch
signaling such as Hairy enhance of split (HES), NF-kB, Hairy/enhancer
of split related with YPRW motif (Hey), vascular growth factor receptor
(VEGF), CYCLIND1, Akt, p21, mammalian target of rapamycin (mTOR),
p27, and c-Myc [19]. HES family including HES1, -5, and -7 subtypes are
primary targets of Notch that act as a transcriptional repressor and
negatively regulate downstream target genes. Potential target genes of
HES1 are CD4, p21, and HES1 itself [106]. A study on miRNA-140-5p
has shown that the expression level of this miRNA is decreased in
gastric cancer. MiRNA-140-5p is a tumor suppressor factor that exerts its
function on the Notch pathway by suppressing Thymus cell antigen 1
(THY1; known as CD90), a tumor-promoting factor with high expression
in gastric cancer. By activation of Notch signaling, its downstream target
genes HES1 and HES5 are increased which subsequently regulate their
targets. HES1 and HES5 prevent apoptosis by upregulation of Bcl-2 and
downregulation of Bax and caspase-3. Therefore, miRNA-140-p5 nega-
tively affects the Notch pathway to inhibit gastric cancer cell progres-
sion through induction of apoptosis [107]. Similarly, a study on miRNA-
Table 1
The function of different types of Notch in cancer.
Notch
receptor
Cancer type Function Ref.
Notch1 Breast cancer Invasion, poor overall survival [53]
Gastric carcinoma Tumor aggressiveness, poor
survival rate, invasion,
migration
[54]
Lung cancer Tumor suppressor (inducing cell
cycle arrest, apoptosis, and
suppressing proliferation, cell
growth, EMT, metastasis)
[55–58]
Oncogene (apoptosis inhibition,
pro-survival effects under
hypoxia, proliferation, poor
survival, colony formation, EMT,
metastasis)
[59–63]
T cell acute
lymphoblastic
leukemia/lymphoma
Growth, survival [64]
Prostate cancer Growth, proliferation, invasion,
tumor sphere formation,
metastasis
[65]
Colorectal cancer Invasion,
tumor–node–metastasis, lymph
node metastases, poor overall
survival
[66]
Head and neck
squamous cell
carcinomas
Both tumor inhibitor and
oncogene
[67]
Ovarian cancer Sphere formation, chemo-
resistance, increasing expression
of cancer stem cells-associated
genes
[68]
Tongue cancer Tumor stage, differentiation,
proliferation, invasion,
metastasis, apoptosis inhibition
[69]
Notch2 Breast cancer Cellular dormancy,
hematopoietic stem cell
mimicry, mobilization in bone
[70]
Gastric cancer Proliferation, growth, colony
formation, invasion, migration
[71]
Colorectal cancer Tumor suppressor [72]
Bladder cancer Tumor growth, EMT, metastasis,
cell-cycle progression, stemness
[73]
Liver cancer stem cells Stemness, clinical severity and
prognosis, self-renewal
[74]
Pancreatic
intraepithelial
neoplasia/pancreatic
ductal
adenocarcinoma
Tumor progression, prolongs
survival, malignant
transformation
[75]
Medullary thyroid
cancer
Tumor suppressor, induction of
apoptosis
[76]
Bladder cancer Proliferation, invasion,
metastasis
[77]
Tongue squamous cell
carcinoma
Proliferation, invasion,
migration
[78]
Esophageal carcinoma Proliferation, migration,
tumorigenicity
[79]
Notch3 Colorectal cancer Tumor formation, proliferation,
proliferation, clonogenic
capacity, aggressive phenotype
[80]
Breast cancer Self-renewal, invasion,
metastatic growth, poor
outcome, proliferation
[81,82]
Ovarian high-grade
serous carcinoma
Recurrent post-chemotherapy,
reduced overall survival, worse
clinical outcome, shortened
progression-free survival,
carboplatin resistance
[83]
Lung cancer Both tumor suppressor and
oncogene
[84]
Gastric cancer Good prognostic biomarker, low
inltration of CD8+T cells, high
inltration of
immunosuppressive cells
[85]
(continued on next page)
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1156
340 has conrmed the anti-cancer function of this miRNA inducing
apoptosis and suppressing proliferation in osteosarcoma cancer cells. To
function, miRNA-340 inhibits b-catenin (cadherin-associated protein) 1
(CTNNB1). Crucial for cell-to-cell junctions and regulation of gene
transcriptions, CTNNB1 is necessary for the function of Wnt signaling
pathway. As Wnt signaling is connected to a wide range of cellular
pathways, dysregulation of CTNNB1 is relevant to a variety of disorders,
especially cancer metastasis. In this study, the authors have shown that
miRNA-340 suppresses CTNNB1 to decrease its targets including HES1
protein of Notch signaling. Overall, miRNA-340 induces apoptosis by
upregulating pro-apoptotic factors (Bim and Bax) and antiapoptotic
proteins (Bcl-2) downregulation while inhibiting proliferation through
suppressing Notch via inactivation of CTNNB1 [108].
In addition to proliferation, Notch signaling is also involved in cancer
invasion and metastasis. Activation of EMT in cancer cells is crucial for
their survival, invasion, and metastasis to other organs. Certain molec-
ular mechanisms are required to induce EMT. During EMT, E-cadherin is
decreased while N-cadherin and vimentin are increased in expression.
Furthermore, other factors include the extracellular matrix (e.g., TGF-b
and Wnt) as well as paracrine signals that mediate the activation of EMT-
inducing transcription factors including zinc-nger E-box (ZEB) proteins
1 and 2, Snail, Slug, and Twist. These factors are responsible for the
induction of EMT, and subsequent invasion and metastasis. During EMT,
cells lose their cell-to-cell adhesion, leading to entry into the blood-
stream through blood vessels [109–112]. Based on conrmed evidence,
Notch is one of the critical regulators of EMT. For instance, NICD targets
snail1 via directly interacting with its promoter region and increasing
EMT. Moreover, Notch affects various signaling pathways and factors (e.
g., NF-kB and integrins) to increase EMT and to incur metastasis and
invasion [113].
MiRNA-873-5p is a tumor suppressor factor with a down-regulated
expression in cervical cancer. MiRNA-873-5p suppresses cancer cell
proliferation and induces apoptosis. Moreover, one study demonstrates
that ZEB1 is one of the target genes of miRNA-873-5p. Indeed, miRNA-
873-5p binds to the 3′-UTR region of ZEB1 to suppress its activities
including invasion and metastasis. Furthermore, one of the ZEB1 targets
is Notch signaling proteins such as Jagged1, Hey1, and Maml2, and
ZEB1 which increase invasion and metastasis by activating the Notch
pathway. Overall, miRNA-873-5p exerts an inhibitory effect on metas-
tasis and invasion of ovarian cancer cells by suppressing ZEB1, leading
to a subsequent inhibition of the Notch pathway [114]. Another
example of targeting EMT by Notch results in increasing metastasis as
studied by Li et al. They show that the tumor suppressor activity of
miRNA-139-5p on glioma via targeting Notch1 signaling. Notch is sup-
pressed via miRNA-139-5p which ultimately leads to the depletion of
Snail to enhance EMT, invasion, and metastasis. Besides, the activity of
miRNA-139-5p decreases the expression of N-cadherin, vimentin, and
bronectin, while increasing E-cadherin [115].
Similarly, another study on the role of miRNA-424-3p was done by
Chen et al. using pituitary adenoma cells. They have demonstrated that
overexpression of miRNA-424-3p inhibits EMT, proliferation, and
metastasis via negatively targeting Jagged1 and subsequently
decreasing matrix metalloproteinase2 (MMP2) and vimentin [116].
MMPs are a group of zinc-dependent proteolytic metalloenzyme pro-
teins that degrade the extracellular matrix during physiological (such as
wound healing) and pathological situations (such as cancer). Based on
their substrate specicity, MMPs are classied into different groups
including matrilysins, collagenases, stromelysins, and membrane-type
MMPs [117–119]. The ability of Notch in targeting MMPs is demon-
strated in previous studies [120–122]. In vitro, miRNA-130b-3p sup-
presses DLL1, MMP9/13, and VEGF in order to hamper invasion and
metastasis in breast cancer [123].
An interesting study carried out by Kawasaki et al. on laryngeal
cancer patients with or without nodal metastasis, reveals that miRNA-
449a has a low expression level in nodal metastasis conditions
compared to the group without nodal metastasis. They also found that
aberrant expression of miRNA-449a is associated with decreased inva-
sion, metastasis, and proliferation via targeting Notch1/2. Moreover,
they concluded that miRNA-449a could be a promising diagnostic
biomarker and a novel therapeutic target for laryngeal cancer patients
with nodal metastasis [124]. Furthermore, miRNA-34a reversely targets
Notch1 and its ligand, Jagged1, to suppress colon cancer cell growth,
invasion, and metastasis. By targeting Notch1, miRNA-34a down-regu-
lates vimentin and bronectin in cancer cells [125]. Another experiment
shows that the overexpression of miRNA-1179 leads to the inhibition of
Notch1/4 and HES1, the Notch downstream target, thereby suppressing
proliferation, invasion, and metastasis. Besides, the study suggests that a
low level of miRNA-1179 is associated with lymph node metastasis, poor
survival rate, and advanced clinical stage [126]. On the contrary,
miRNA-1275 exerts oncogenic roles in lung adenocarcinoma. To exert
its carcinogenic functions, miRNA-1275 activates Wnt/b-catenin and
Notch signaling pathways and promotes stemness, recurrence, and
metastasis. Moreover, HIF-1a was identied as the inducer of miRNA-
1275 [127–131]. Intriguingly, miRNAs that target the Notch pathway
that increases metastasis of cancer cells could be introduced to these
cells via nanocarriers. Besides, triple-negative breast cancer cells express
high levels of Notch1 on their surface and using Notch1-antibody for
delivering anti-cancer miRNAs has revealed promising results. In an
effort, it was demonstrated that poly(lactic-co-glycolic acid) nano-
particles containing miRNA-34a which were modied with Notch 1
antibodies could signicantly inhibit breast tumor cells migration and
proliferation and induce cell senescence [132].
Another hallmark of cancer crucial for tumor cell survival and spread
is angiogenesis. Accumulating evidence conrms the importance of the
Table 1 (continued )
Notch
receptor
Cancer type Function Ref.
(regulatory T cells and M2
polarized macrophages),
increasing the expression level of
immune checkpoint inhibitors,
immune tolerance
Prostate cancer Proliferation, colony formation [86]
Pancreatic cancer Gemcitabine resistance, caspase-
induced apoptosis inhibition
[87]
Notch4 Endometrial cancer Tumor suppressor [88]
Breast cancer Proliferation, invasiveness,
increasing tumor volume, lymph
node metastasis, advanced
tumor metastasis stage, cancer
recurrence, aggressive
clinicopathological and
biological phenotypes, poor
prognosis
[89,90]
Prostate cancer Tumor cell viability,
proliferation, growth, apoptosis
inhibition, cell metastasis,
invasion
[91]
Gastric cancer Tumor cells growth,
proliferation
[92]
Colorectal cancer Lympho-vascular invasion, poor
overall survival, prognostic
biomarker
[93]
Head and neck
squamous cell
carcinoma
Proliferation, cisplatin
resistance, inhibition of
apoptosis, and cell-cycle
dysregulation, EMT, invasion,
metastasis
[94]
Pancreatic cancer Viability, migration, invasion,
docetaxel resistance
[95]
Salivary adenoid cystic
carcinoma
Invasion, metastasis, recurrence [96]
Melanoma Tumor suppressor,
mesenchymal-epithelial
transition, inhibition of invasion
and metastasis
[97]
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International Journal of Biological Macromolecules 222 (2022) 1151–1167
1157
regulatory role of Notch in physiological and pathological angiogenesis
[133–135]. Moreover, a dysfunctional form of Jagged1 is seen in several
vascular anomalies, including embryonic lethal and embryonic hemor-
rhage. Further, the lack of Hey1/2 resulted in small vessels with no more
development. Various studies have indicated that VEGF induces the
Notch pathway by increasing angiogenesis via activation of other
pathways such as PI3K/Akt. Interestingly, activation of the Notch
pathway could also suppress angiogenesis. For instance, Notch4 has
been reported to attenuate angiogenesis via suppressing VEGF. Thus,
both pro-angiogenic and anti-angiogenic activities have been reported
for the Notch pathway [136–139].
MiRNAs are involved in the angiogenesis process by targeting Notch
signaling. As an example, miRNA-34a is involved in the differentiation
of CD133+glioma stem cells into vascular endothelial cells via sup-
pressing the Notch pathway [140]. Another role of miRNA has been
suggested in retinal angiogenesis by targeting the Notch1 pathway
[141]. However, despite the critical role of Notch signaling in tumor
angiogenesis, several studies point to the regulatory role of this pathway
in association with miRNAs to affect tumor angiogenesis. Jeon et al.
shows an interaction between glioma initiating cells and endothelial
cells leading to cancer progression. They have shown that activation of
nitric oxide synthase via platelet-derived growth factor (PDGF) in both
cells leads to overexpression of nitric oxide-dependent inhibitor of
differentiation 4 (ID4). Upregulation of ID4 mediates suppression of
miRNA-129 to increase the activation of the Jagged1-Notch pathway
and HES1. Activation of the Notch pathway ultimately promotes glioma-
initiating cells' self-renewal and tumor angiogenesis. These results are
important as anti-cancer rationale therapies that target the Notch
pathway (Fig. 3) [142].
4.2. Therapy response
A major challenge for cancer therapy, chemo-resistance is also
responsible for the failure of anticancer drugs in suppressing tumor
progression. Different mechanisms are involved in chemo-resistance
including overexpression of genes responsible for increasing drug
resistance (such as multidrug resistance gene (MDR1)), mitochondrial
alteration, drug efux transporter pumps (such as P-gp), autophagy, as
well as cellular signaling pathways and factors (such as growth factors,
NF-κB, JAK/STAT3, PI3K/Akt/mTOR, and MAPK/ERK). Besides, DNA
repair mechanisms are also involved in drug resistance. There are
different mechanisms by which DNA undergoes repair following damage
including nucleotide and base excision repair, homologous recombina-
tion, and mismatch repair. Furthermore, the role of tumor microenvi-
ronment is also important in developing chemo-resistance. For instance,
hypoxia, pH, and paracrine signals can affect response of tumor cells to
Fig. 3. The role of miRNAs in regulating cancer progression via targeting the Notch signaling pathway.
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1158
therapy [143–147]. Various studies have revealed the critical function
of Notch signaling in regulating chemo-resistance [148–150]. Islam
et al. investigates chemo-resistance in head and neck squamous cell
carcinoma and shows that the mutated form of Keap1 is key in devel-
oping chemo-radio resistance in cancer which results from the activation
of Notch signaling pathway. Keap1 suppresses Nrf2 function and nuclear
translocation. Inhibition of Keap1 resulted in the activation of Nrf2, its
translocation into nucleus, and subsequently overexpression of its
downstream target genes. This study shows that activation of Nrf2
following mutation in Keap1, leads to overexpression of its downstream
target, Notch, which causes cellular metabolic reprogramming that ac-
celerates clonal expansion. This further leads to gaining self-renewal
abilities that induce signaling pathways responsible for therapy resis-
tance [151]. Congruent with this study which addressed the role of
Notch receptor in chemo-resistance, another research demonstrates that
Notch ligands are also involved. Kumar et al. has shown that DLL1
ligand overexpression is associated with NF-κB activation followed by
increased chemo-resistance [152]. A review by Kumar et al. discusses
the crosstalk between Notch and two pathways of Hedgehog and Wnt.
HES1, Jagged1, and other components of Notch signaling pathway can
regulate Hedgehog in mediating chemo-resistance via targeting Gli
factors. However, Wnt signaling could be suppressed by Notch [153]. It
is accepted that miRNAs also play a role in the regulation of key cellular
processes such as Notch signaling to confer chemo-resistance. For
instance, overexpression of miRNA-628-5p is associated with Jagged1
suppression in prostate cancer. For this, miRNA-628-5p directly binds to
the 3′UTR region of Jagged1 and suppresses Notch, Snail and Slug to
decrease EMT. Moreover, miRNA-628-5p activity ultimately results in
the inhibition of chemo-resistance in cancer cells under enzalutamide
and docetaxel's pressure [154]. In vitro, Notch1 suppresses miRNA-451
via the AP-1 transcription factor. MDR-1 is the downstream target of
miRNA-451 by which miRNA-451 increases the sensitivity of lung
adenocarcinoma cells under docetaxel therapy [155]. Further, the
impact of miRNA-34 in cancer chemo-resistance occurs through tar-
geting Notch signaling pathway as shown in several studies [156–159].
MiRNA-34a is a tumor suppressor and is downregulated in breast cancer
cells after treatment with mutated form of p53 or p53 RNAi. MiRNA-34a
suppresses Notch1 to sensitize breast cancer cells to doxorubicin.
Additionally, miRNA-34a overexpression is associated with decreased
cancer stemness and a small tumor size [129]. Another study on miRNA-
34a demonstrates that its ectopic overexpression leads to sensitivity of
breast cancer cells to Adriamycin via targeting the 3′UTR region of
Notch1 [160]. Furthermore, miRNA-34a overexpression suppresses
migration and invasion of breast cancer cells via Snail inhibition, but not
their growth. The administration of doxorubicin along with miRNA-34a
notably induces apoptosis and leads to the reduction of proliferation in
cancer cells. Besides, inhibition of Snail following miRNA-34a over-
expression results in an inhibition of Notch/NF-κB pathway as well as
the RAS/RAF/MEK/ERK axis which subsequently leads to drug resis-
tance suppression [161].
Likewise, miRNA-195-5p is downregulated in colorectal cancer cells.
Upregulation of miRNA-195-5p suppresses Notch2 and RBPJ to increase
sensitivity of cancer cells to 5-uorouracil. Besides, stem-like capacity of
cells, stemness, and tumor sphere formation is decreased while
apoptosis is induced following the miRNA-195-5p overexpression [162].
Another study shows that increased expression of miRNA-199b-5p
negatively regulate Jagged1 expression in ovarian cancer in order to
increase cisplatin-induced cytotoxicity [163]. Additionally, miRNA-136
targets Notch3 reversely and mediates the reduction of cell viability,
tumor cells proliferation, angiogenesis, spheroid formation of cancer
stem cells, and induction of apoptosis in paclitaxel resistant ovarian
cancer cells. In fact, miRNA-136 decreases the resistance of cancer cells
to paclitaxel therapy by reducing the expression levels of survivin, S6,
BCL2, BCL-Xl, Cyclin D1, NF-κB, while increasing that of Bid, Bax, and
Bim proteins [164]. In hepatocellular carcinoma, miRNA-760 over-
expression suppresses doxorubicin resistance via targeting Notch1/
HES1 pathway. Besides, upregulation of miRNA-760 augments PTEN
overexpression and decreases Akt phosphorylation [165].
In addition to chemo-resistance, nding a solution for increasing the
sensitivity of cancer cells to radiotherapy is important. Radiation ther-
apy leads to induction of DNA damage either directly or indirectly via
increasing free radicals. Various studies have shown the key role of
Notch signaling in regulation of radio-resistance, as Notch has critical
crosstalk with oncogenic cellular signaling pathways. Besides, other
studies show that some cancers have increased levels of Jagged1 on the
surface and Notch1 in the culture media following irradiation
[166–172]. Similarly, miRNAs also play key roles in regulating the
response of cancer cells to radiation via targeting the Notch pathway.
For instance miRNA-124-3p suppresses Notch related proteins to pro-
mote radiation-induced apoptosis in nasopharyngeal carcinoma.
Furthermore lncRNA PTPRG-AS1 acts as an inhibitor of miRNA-124-3p
in order to increase radio-sensitivity [173]. MiRNA-153 has been shown
to sensitize pancreatic cancer cells to radiation therapy via targeting
Jagged1 [174]. Interestingly, in a study by Yang et al., miRNA-3163
negatively targets ADAM17, a factor responsible for activation of
Notch pathway, to mediate therapy resistance. MiRNA-3163 suppresses
Notch signaling pathway via targeting ADAM17, and promotes the
sensitivity of hepatocellular carcinoma cells to targeted agents (Fig. 4)
[175].
5. Regulation of Notch signaling pathway by lncRNAs in cancer
5.1. Cancer progression
In contrast to miRNAs, numerous studies have associated lncRNAs
with Notch signaling pathway and tumor progression. For instance, the
results of a study have revealed that lncRNA MEG3 is overexpressed in
breast cancer and enhances tumor progression. DNA methyltransferase-
1 suppresses MEG3 expression via inhibiting the hypermethylation of
the MEG3 promoter, thereby decreasing tumor proliferation, and
inducing apoptosis. Besides, Notch1 is the downstream target of MEG3
to induce EMT [176]. LncRNA ILF3-AS1 is another oncogenic factor
highly expressed in hepatocellular carcinoma. ILF3-AS1 increases can-
cer cell viability, EMT, invasion, and migration. For this, ILF3-AS1
competes with Meis Homeobox 2 (MEIS2) to suppress miRNA-628-5p
and increase Notch signaling pathway activities [177]. Another
example is lncRNA PTTG3P which suppresses miRNA-142-5p to pro-
mote Jagged1 overexpression, followed by Notch1 activation. Down-
stream targets of Notch including vimentin, c-Myc, Snail, Twist, and
Cyclin D1 are increased, which result in increased EMT, aggressiveness,
proliferation, and migration of tongue cancer cells [178]. LncRNA
LINC01806 attenuates miRNA-4428 expression to promote Notch2
signaling pathway and subsequently accelerate non-small cells of lung
cancer progression [179]. In contrast to these studies, He et al. has
shown that lncRNA DLEU2 enhances cervical tumor cells proliferation
and progression of cell cycle via inhibiting Notch signaling. to do this,
lncRNA DLEU2 suppresses p53 expression via interacting with ZFP36
Ring Finger Protein (ZFP36) [180]. However, another study shows that
lncRNA DLEU2 induces Notch signaling and increase tumor progression.
The authors of this study have demonstrated that lncRNA DLEU2
expression increases by STAT1, which in turn suppresses miRNA-23b-3p
to increase Notch2, thereby increasing gastric cancer cells proliferation,
invasion, and migration [181].
Furthermore, lncRNA MIR99AHG is overexpressed in pancreatic
cancers mediated by transcription factor forkhead box A1 (FOXA1).
Upregulation of this lncRNA results in sequestration of miRNA-3129-5p
and subsequently ELAV-like RNA binding protein 1 (ELAVL1), followed
by activation of the Notch2 signaling pathway. Activation of Notch2
ultimately results in tumor cell proliferation, migration, and invasion
[182]. In melanoma, lncRNA BASP1-AS1 expression increase is associ-
ated with tumor progression, proliferation, invasion, and migration.
LncRNA BASP1-AS1 up-regulates Notch3 expression via interacting with
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1159
YBX1. Activation of Notch3 results in an increase in downstream targets
including c-Myc, CDK4, and PCNA [183]. A group of lncRNAs called
Small nucleolar RNA host genes (SNHGs) host genes of small nucleolar
RNAs. Accumulating evidence has revealed that these lncRNAs are
involved in various disorders such as cancer [184–188]. In a study on
pancreatic cancer cells, it was found that co-culturing of mesenchymal
stem cells and pancreatic cancer cells would increase lncRNA SNHG7 in
tumor cells. Upregulation of lncRNA SNHG7 is further associated with
tumor cell stemness and resistance against Folrinox by targeting the
Notch1/Jagged1/HES1 pathway [189]. SNHG7 could also affect tumor
progression via the miRNA/Notch pathway. For instance, lncRNA
SNHG7 has been proven to sponge miRNA-34a to increase Notch1 and
promote breast cancer progression [190]. As mentioned before, the
progression of tumor cells is increased in hypoxic conditions. In a study,
the authors elucidated that hypoxia could induce the expression of
lncRNAHILAR to promote renal cancer cell invasion and metastasis.
Renal cancer cells release exosomes in response to a hypoxic microen-
vironment that contains lncRNAHILAR. This lncRNA acts as competing
endogenous RNA (ceRNA) to suppress miRNA-613/206/1-1-3p, and
then increases the Jagged1/Notch pathway, followed by activation of C-
X-C motif chemokine receptor 4 (CXCR4). This pathway activity sub-
sequently increases invasive and metastatic capacity of renal cancer cells
[191]. LncRNAs also mediate the response of cancer cells to the immune
system via targeting the Notch pathway. For instance, LINC01355
overexpression is associated with oral squamous cell carcinoma cell
proliferation, invasion, and metastasis. LINC01355 suppresses CD8+T
cell immune response and increases their apoptosis to exert its function
and promote tumor cell progression. For these purposes, INC01355
augments Notch signaling pathway via increasing Notch1, Jagged1, and
HES1 [192]. In the case of angiogenesis, in a study, it was found that
exosomes derived from Jagged1 overexpressed triple-negative breast
cancer cells contained lncRNA MALAT1 which induces angiogenesis in
human vascular endothelial cells via targeting miRNA-140-5p and
subsequently activating the VEGFA pathway [193]. Thus, lncRNAs play
a critical role in cancer progression via targeting the Notch signaling
pathway. Table 2 represents other lncRNAs with proven regulatory
functions on the Notch pathway in cancer.
5.2. Therapy response
As mentioned before, various mechanisms are involved in resistance
to therapy by cancer cells and the Notch signaling pathway could
regulate these mechanisms. For instance, lncRNA SNHG15 suppresses
miRNA-451 to increase MDR1 promotion to mediate resistance to ge-
tinib in lung adenocarcinoma cells [222]. Similarly, lncRNA SNHG7 is
involved in cancer chemoresistance. A study shows the upregulation of
SNGH7 in breast cancer. SNHG7 negatively regulates the expression of
miRNA-34a to increase the percentage of CD44+/CD24- cells, stemness
(via targeting Oct4, SOX2, and Nanog), and sphere formation. Besides,
this interaction between lncRNA SNHG7 and miRNA-34a results in a
higher sensitivity response to chemo-resistance in breast cancer cells
[223]. It has been reported that Notch1 expression is increased in
cisplatin-resistant gastric cancer cells. Notch1 promotes the expression
of lncRNA AK022798 to increase multidrug resistance-associated pro-
tein 1 (MRP1) and P-gp while decreasing caspase 3/8 to suppress
apoptosis. Overall, Notch1 increases cisplatin resistance via targeting
lncRNA AK022798 [224]. In another study, it was demonstrated that
lncRNA DANCR acts as ceRNA for miRNA-34a-5p to increase Jagged1.
Fig. 4. The role of miRNAs in regulating therapy response via targeting the Notch signaling pathway.
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1160
Table 2
The function of different lncRNAs in cancer via targeting Notch.
lncRNA Cancer type Signaling
network
Remark Ref
SNHG11 Lung
adenocarcinoma
miRNA-
193a-5p/
Notch3
SNHG11
overexpression
suppresses miRNA-
193a-5p to increase
Notch3 in promoting
tumor growth,
proliferation and
migration.
[194]
SNHG3 Ovarian cancer miRNA-
139-5p/
Notch1
SNHG3 upregulation
resulted in miRNA-
139-5p suppression,
followed by
activation of Notch1
pathway in increasing
proliferation and
migration.
[195]
SNHG3 Breast cancer miRNA-
154-3p/
Notch2
SNHG3 sponges
miRNA-154-3p to
increase Notch2
activation and
subsequently
promoting tumor
cells proliferation,
viability, invasion
and migration.
[196]
SNHG22 Gastric Cancer EZH2
miRNA-
200c-3p/
Notch1
ELK4 increases the
expression of
SNHG22.
SNHG22 targets
EZH2 to inhibit onco-
suppressor genes
expression.
For increasing the
expression level of
Notch1, SNHG22
sponges miRNA-
200c-3p, thereby
increasing
proliferation and
invasion.
Overexpression of
SNHG22 is associated
with poor prognosis.
[197]
SNHG12 Endometrial
cancer
ZIC2/
SNHG12/
Notch
ZIC2 up regulates
SNHG12 and
subsequently Notch
signaling pathway in
increasing tumor cells
proliferation,
migration, and
invasion.
[198]
SNHG12 Nasopharyngeal
carcinoma
Notch1 Increased level of
SNHG12 is associated
with clinical stage,
grade and poor
prognosis.
SNHG12 increases
proliferation,
migration and
invasion of cancer
cells via activating
Notch1 pathway.
[199]
LINC01410 Glioma miRNA-
506-3p/
Notch2
LINC01410
expression is
increased in glioma
cells via Myc.
Overexpressed
LINC01410
suppresses miRNA-
506-3p to increase
Notch2 in promoting
cancer progression.
[177]
SRA Ovarian cancer Notch [200]
Table 2 (continued )
lncRNA Cancer type Signaling
network
Remark Ref
Upregulation of SRA
is associated with
increased tumor
growth, invasion, and
migration via
targeting Notch
pathway.
HOXA-AS2 Cervical cancer RBP-JK/
Notch
HOXA-AS2 increases
Notch signaling
pathway via targeting
RBP-JK to promote
tumor progression.
[201]
HCG11 Pancreatic
carcinoma
miRNA-
579-3p/
MDM2/
Notch/
Hes1
HCG11 suppresses
miRNA-579-3p to
increase MDM2 and
subsequently Notch/
Hes1.
Activation of Notch/
Hes1 resulted in high
aggressiveness and
tumor progression.
[202]
FTX Colorectal cancer miRNA-
214-5p/
Jagged1
FTX suppresses
miRNA-214-5p to
increase Jagged1 and
promote
proliferation,
migration, and
invasion.
[203]
MEG8 Hemangioma miRNA-
203/
Jagged1/
Notch1
MEG8 overexpression
promotes Jagged1/
Notch1 pathway via
inhibition of miRNA-
203 in order to
increase proliferation
and invasion.
[181]
MEG3 Endometrial
carcinoma
Notch1/
HES1
MEG3 overexpression
inhibited tumor cells
proliferation and
growth via
suppressing Notch1/
HES1 signaling
pathway.
[204]
HAGLROS Esophageal
cancer
miRNA-
206/
Notch3
HAGLROS promotes
proliferation,
invasion and
metastasis via
targeting miRNA-206
and subsequently
Notch3.
[205]
UCA1 Tongue cancer miRNA-
124/
TGFβ1/
Jagged1/
Notch1
UCA1 is
overexpressed in
tongue cancer and
targets miRNA-124/
TGFβ1/Jagged1/
Notch1 pathway to
increase EMT and
invasion.
UCA1 upregulation is
associated with
poorer prognosis.
[206]
GHET1 Prostate cancer KLF2/HIF-
1
α
/Notch1
Overexpression of
CHET1 is associated
with increased cell
proliferation via
suppression of KLF2
and subsequently
increased HIF-1
α
/
Notch1axis.
Knockdown of CHET1
is associated with cell
cycle arrest at G0/G1
phase and enhanced
apoptosis.
[207]
FEZF1-AS1 Glioblastoma Upregulation of
FEZF1-AS1 is
[208]
(continued on next page)
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1161
Table 2 (continued )
lncRNA Cancer type Signaling
network
Remark Ref
miRNA-
34a/Notch-
1
associated with poor
survival.
FEZF1-AS1 inhibits
miRNA-34a to
increase Notch1 in
promoting invasion
and migration.
FEZF1-AS1 Non-small cell
lung cancer
miRNA-
34a/
Notch1
FEZF1-AS1
overexpression
suppresses miRNA-
34a to increase
Notch1 function.
Upregulation of
FEZF1-AS1 is
associated with tumor
cells invasion and
metastasis, while
decreased apoptosis.
[209]
PlncRNA-1 Glioma Jagged1/
Notch1/
HES1
PlncRNA-1 upturning
leads to activation of
Jagged1/Notch1/
HES1 axis in
increasing cancer
cells proliferation and
colony formation,
while suppressing
apoptosis.
[210]
XIST Non-small cell
lung cancer
miRNA-
137/
Notch1/
TGF-β1
XIST sponges miRNA-
137 to promote TGF-
β1 activity in
increasing EMT.
MiRNA-137
suppresses Notch1
pathway.
[211]
LET Non-small cell
lung cancer
NICD1 LET expression is
down regulated in
cancer cells.
Downregulation of
LET is associated with
advanced tumor
stages and poor
overall survival.
Overexpression of
LET leads to
suppression of
proliferation,
invasion, and
metastasis, while
enhance cell cycle
arrest and apoptosis
via suppressing
NICD1.
[212]
HNF1A-
AS1
Oral squamous
cell carcinoma
STAT3/
HNF1A-
AS1/
Notch1/
HES1
As an upstream
mediator, STAT3
increase the
expression of HNF1A-
AS1.
Upregulation of
HNF1A-AS1 resulted
in activation of
Notch1/HES1
pathway in increasing
cancer cells
proliferation,
migration and EMT.
[213]
FAM83H-
AS1
Colorectal
carcinoma
Jagged1/
Notch1
Upregulation of
FAM83H-AS1 is
associated with
clinical features and
poor prognosis.
FAM83H-AS1
increased cell
proliferation and
migration, while
suppressing apoptosis
[214]
Table 2 (continued )
lncRNA Cancer type Signaling
network
Remark Ref
via activation of
Jagged1/Notch1.
HOTAIR Cervical cancer Notch/Wnt HOTAIR
overexpression is
associated with
lympho-vascular
invasion, tumor size,
and lymph node
metastasis.
HOTAIR
overexpression leads
to enhanced tumor
growth, proliferation,
EMT, and invasion via
targeting Notch-Wnt
signaling pathway.
[215]
HOTAIR Pancreatic cancer miRNA-
613/
Notch3
HOTAIR
overexpression
suppresses miRNA-
613 to increase
Notch3 pathway.
Upregulation of
HOTAIR is associated
with tumor
differentiation,
advanced TNM stage,
nodal metastasis,
poor survival,
proliferation,
invasion and
migration.
Downregulation of
HOTAIR resulted in
tumor cells apoptosis
and cell cycle arrest at
G0/G1 phase.
[216]
ZFAS1 Glioma Notch Overexpression of
ZFAS1 is associated
with advanced tumor
stage and poor
survival rate.
ZFAS1 promotes
cancer cells
proliferation, EMT,
invasion and
migration via
activation of Notch
signaling pathway.
[217]
DSCAM-
AS1
Colorectal cancer miRNA-
137/
Notch1
DSCAM-AS1
suppresses miRNA-
137 to increase
Notch1, thereby
promoting
proliferation,
migration, and EMT.
[218]
MIR22HG Gastric cancer Notch2/
HEY1
MIR22HG is down
regulated in gastric
cancer and its
overexpression leads
to suppression of
Notch2 and HEY1.
Low expression level
of MIR22HG is
associated with poor
overall survival.
Upregulation of
MIR22HG resulted in
suppression of tumor
cells proliferation,
invasion and
migration.
[219]
Linc00514 Breast cancer Jagged1/
Notch/IL4
and IL-6
Linc00514 is
overexpressed in
breast cancer and
promotes Notch
[220]
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International Journal of Biological Macromolecules 222 (2022) 1151–1167
1162
This axis ultimately leads to docetaxel resistance in prostate cancer cells
[225]. Furthermore, another study has revealed that lncRNA MALAT1
interacts with Notch1 to promote ovarian cancer cells' resistance to
cisplatin. Following the knockdown of lncRNA MALAT1, Bax upregu-
lation and Bcl-2 downregulation occur in response to cisplatin [226].
LINC00152 is another lncRNA that mediates drug resistance via
targeting the Notch signaling pathway. LINC00152 sponges miRNA-
139-5p to increase Notch1 expression level. Activation of Noth1 pro-
motes resistance of colorectal cancer cells to 5-uorouracil [227].
Another long intergenic noncoding RNA named LINC00021 targets
Notch signaling pathway and suppresses p21 via affecting EZH2 to in-
crease chemo-resistance to temozolomide in glioblastoma cells [228]. In
the case of radio sensitivity, few studies address the role of lncRNAs in
regulating resistance/sensitivity of cancer cells to radiation therapy. An
example is lncRNA AGAP2-AS1 which is involved in increasing the
resistance of lung cancer cells to radiation therapy. For this purpose, M2
polarized macrophage-derived exosomes containing AGAP2-AS1 sponge
miRNA-296 to increase Notch2 to enhance radio-resistance [229].
6. Regulation of Notch signaling pathway by other ncRNAs in
cancer progression and therapy
The tRFs are a group of ncRNAs and accumulating research has
revealed their critical roles in cancer. They regulate gene expression,
gene silencing, protein translation, and RNA processing, thereby con-
trolling vital cellular processes such as cell proliferation and differenti-
ation. Moreover, their function in different cancers including breast
cancer, prostate cancer, leukemia, and lung and colorectal cancers is
elucidated [230]. Like miRNAs and lncRNAs, tRFs exert two different
functions of tumor suppression or promotion in cancers. By regulating
the expression of tumorigenic factors, tRFs could enhance cancer cell
proliferation and progression. Different tRF mechanisms exert their
functions in cancer cells such as suppressing the transcription process,
enhancing ribosomal protein's translation, and increasing the function of
mitosis regulators such as aurora kinase A [231]. Additionally, they
could also target invasion and metastasis, and are considered promising
biomarkers for cancer diagnosis and prognosis [232–235]. Huang et al.
has a well-performed study to illustrate the role of tRFs in cancer by
targeting the Notch signaling pathway. They evaluate the effect of tRF/
miRNA-1280 on colorectal cancer stem-like cell progression. A 17-bp
fragment, tRF/miRNA-1280, is derived from tRNA
Leu
and has a low
expression in colorectal cancer. As a tumor suppressor factor, tRF/
miRNA-1280 diminishes tumor cell proliferation, colony formation,
and metastasis via negatively regulating JAG2. Moreover, suppression of
Notch by tRF/miRNA-1280 results in cancer stem-like cell phenotypes
inhibition, as well as Gata1/3 and miRNA-200b transcriptional sup-
pression. Suppression of miRNA-200b leads to decreased levels of SUZ12
and ZEB1 [236].
Another class of ncRNAs is circRNAs with critical functions in cancer
[237–240]. It is demonstrated that circNFIX has a high expression level
in glioma. CircNFIX inhibits miRNA-34a to increase Notch1 to enhance
tumor cell proliferation and migration. Moreover, suppression of
circNFIX or upregulation of miRNA-34a is associated with cell apoptosis
[241]. In another study, it was shown that hsa_circ_0009910 over-
expression in ovarian cancer cells is associated with miRNA-145
downregulation which increase NF-kB and Notch/HES pathway acti-
vation. Activation of these pathways promotes tumor proliferation and
migration. Moreover, upregulation of hsa_circ_0009910 leads to an un-
favorable prognosis in cancer patients [242].
Another circRNA is circKIF4A (hsa_circ_0007255) which suppresses
miRNA-375/1231 in order to enhance bladder cancer cells progression
via increasing Notch2 [243]. Furthermore, hsa_circ_0058124 is associ-
ated with poor prognosis, increased papillary thyroid cancer cell pro-
liferation, invasion and metastasis via suppressing miRNA-218-5p.
Inhibition of miRNA-218-5p leads to upregulation of NUMB, a strong
inhibitor of Notch, which subsequently suppresses the Notch3/
GATAD2A axis [244].
The results of another experiment have revealed that circAPLP2 at-
tenuates miRNA-103-3p expression to increase colorectal cancer cells
proliferation and metastasis via activation of the Notch signaling
pathway [245]. Additionally, circ-NSD2 suppresses miRNA-199b-5p to
promote colorectal cancer cell metastasis and migration via increasing
Jagged1 and discoidin domain receptor tyrosine kinase 1 (DDR1)
expression [246].
Circular RNA FAT atypical cadherin 1 (circFAT1) expression has
been shown to be increased in breast cancer cells. In one study, it was
founded that overexpression of circFAT1 is associated with oxaliplatin
resistance via sponging miRNA-525-5p to increase spindle and
kinetochore-associated complex subunit 1 (SKA1). This axis ultimately
results in the activation of Notch and Wnt signaling pathways and de-
creases the sensitivity of breast cancer cells to oxaliplatin therapy [247].
7. Conclusion and remarks
Cancer is characterized by uninhibited growth and proliferation of
cells resulting from disrupted mechanisms that highly control cell di-
vision. Numerous studies have focused on various cell signaling path-
ways to bring cancer under control it remains hard to treat.
Conventional cancer therapies include surgeries, chemotherapies, and
radiation therapies. However, resistance to therapeutics by cancer cells
and recurrence is one of the obstacles in cancer therapy and remains to
be solved. Notch is an important signaling pathway that affects vital cell
processes such as proliferation, differentiation, invasion, and metastasis.
Notch is a cell membrane receptor and is activated after binding to its
ligands. Following activation, a part of Notch receptor named NICD is
separated and transferred to the nucleus to regulate its downstream
target genes and its degradation is mediated by proteasomes. Regulation
of Notch signaling is of importance for cancer therapy. The most known
class of ncRNAs is miRNAs are 22 nucleotides long. MiRNAs regulate
gene expression, protein translation, and function. Additionally, they
target various cellular signaling to affect tumorigenesis and response to
therapy by cancer cells. Another class of ncRNAs is lncRNAs with at least
200 nucleotides and critical functions in cells. It is highly accepted that
these ncRNAs are important regulators of cancer, and affect signaling
pathways to induce tumorigenesis or act as a tumor suppressor. One of
the pathways under the control of these ncRNAs is the Notch signaling
pathway. ncRNAs could induce or inhibit this pathway to regulate
cancer hallmarks. For instance, ncRNAs affect Notch and its downstream
targets to regulate apoptosis via mitochondrial pathways. Likewise, they
Table 2 (continued )
lncRNA Cancer type Signaling
network
Remark Ref
signaling pathway to
increase IL-4 and IL-6.
Overexpression of
Linc00514
accelerates tumor
proliferation,
invasion, increasing
the number of
macrophages
expressing M2
markers CD206 and
CD163, tumor size,
and pulmonary
metastatic nodules
NALT Acute
lymphoblastic
leukemia
Notch1 NALT overexpression
increased tumor cells
proliferation and
growth via activation
of Notch1 signaling
pathway through cis-
regulation.
[221]
M. Hashemi et al.
International Journal of Biological Macromolecules 222 (2022) 1151–1167
1163
regulate metastasis and invasion by affecting EMT-TFs, cadherins, and
MMPs. In addition, ncRNAs and Notch are associated with regulation of
tumor angiogenesis, stemness, and cancer recurrence. Intriguingly,
lncRNAs act as ceRNA for miRNA as their upstream mediator to
modulate Notch signaling in cancer. It bears noting that the interaction
between Notch and other ncRNAs such as circRNAs and tRFs are being
investigated. Interestingly, Notch can be an upstream regulator of
ncRNAs to regulate cellular processes. Overall, the relationship between
ncRNAs and the Notch pathway is promising and future studies should
address this issue for overcoming barriers in cancer treatment.
Funding
No funding was received.
CRediT authorship contribution statement
All authors have contributed at least in part in preparing this
manuscript. We conrm that we acknowledge authorship roles.
Declaration of competing interest
The authors declare no conict of interest.
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