Muhammad Tahir Hayat Science Reviews - Biology, 2024, 3(1), 1-8
The Role of Non-Coding RNAs in Cancer Progression:
A Concise Comprehensive Review
Muhammad Tahir Hayat, PhD.
Department of Biotechnology, Faculty of Biological Sciences, Quaid-i-Azam University, 45320, Islamabad, Pakistan;
Received February 28, 2024. Revised March 17, 2024. Accepted March 18, 2024.
Abstract: Cancer is among one of the most widespread diseases globally and poses a great threat to human
wellbeing. Non-coding RNAs (ncRNAs) compose most transcripts but cannot undergo translation. Thus, no
proteins are made by them. However, studies have shown that ncRNAs can mimic both oncogenes and tumour
suppressor genes involved in cancer. This review discusses recent research on the involvement of ncRNAs in
the progression, diagnosis, and treatment of cancer. These ncRNAs consist of microRNAs, long non-coding
RNAs (lncRNAs) and circular RNAs (circRNAs). This concise paper aims to inform researchers, clinicians, and
scientists in navigating the dynamic field of ncRNAs in cancer with the goal of fostering collaboration to
translate discoveries into practical clinical advancements.
Keywords: Non-coding RNAs, cancer, ncRNAs; microRNAs; cancer progression.
Cancer is a global disease considered a contin-
uous threat to the safety and wellbeing of human-
kind due to the large-scale challenges associated
with its diagnosis and treatment. A survey carried
out in the United States identified cancer as the sec-
ond-leading cause of human mortality after heart
disease (Siegel et al., 2019). Decades of research on
the biology of cancer has primarily concentrated on
the role of genes that code for proteins. Only re-
cently was it publicized that a family of molecules
that do not undergo translation, called non-coding
RNAs (ncRNA), also perform a consequential role
in regulating cell-based activities. Since their dis-
covery, the understanding of ncRNA has greatly
advanced, with scientists identifying a diverse and
widespread class of ncRNAs that comprise both
carcinogenic and tumor-suppressive varieties. As a
result, ncRNAs have been used as novel biomarkers
for therapeutics in hundreds of clinical studies fo-
cused on cancer. This review aims to highlight the
appreciable contribution of ncRNAs in cancer biol-
ogy by exploring their complex molecular mecha-
nisms and evaluating their potential contribution to
the accurate diagnosis and effective treatment of
cancer, while advancing current dialogue on medi-
cal advancements in the field of oncology.
Overview and classification of ncRNAs
The central dogma of molecular biology pos-
its that genetic information in the form of DNA is
transcribed into RNA and that RNA is subsequently
translated into proteins. Non-coding RNAs, or
ncRNAs, are functional RNA molecules transcribed
from DNA that are not translated into proteins
(Ding et al., 2021). High-throughput sequencing
technology has revealed that about 98% of the hu-
man genome is transcribed into ncRNAs (Birney et
al., 2007).
There are 15 different classes of ncRNAs that
are further divided into subgroups based on criteria
applied during the classification process, including
endogenous function, size, and capping (Figure 1).
The endogenous function of ncRNAs can be catego-
rized as regulatory ncRNAs and structural (also
called housekeeping) ncRNAs. Regulatory ncRNAs
operate as regulators, taking part in chromatin
Muhammad Tahir Hayat Science Reviews - Biology, 2024, 3(1), 1-8
remodeling, transcription, post-transcriptional pro-
cesses, and signal transmission (Anastasiadou, Ja-
cob, et al., 2018). Housekeeping ncRNAs, like ribo-
somal RNAs (rRNAs) and transfer RNAs (tRNAs),
are engaged in cellular genetic processes including
protein synthesis, RNA modification, and RNA
splicing (Dozmorov et al., 2013).
On the basis of size, ncRNAs can be classified
as long ncRNAs (lncRNAs) (>200 nucleotides (nt))
and small ncRNAs (<200 nt) (Uppaluri et al., 2023).
lnccoding RNAs are characterized as untranslated
RNAs comprised of two subgroups called circRNAs
and pseudogenes (Zhang et al., 2019). There are
three short ncRNAs known to be involved in cancer.
These include piwi-interacting RNAs (piRNAs),
small interfering RNAs (siRNAs), and microRNAs
(miRNAs). Of these, microRNAs are the most prev-
alent and well-researched.
Moreover, ncRNAs exhibit diverse structural
features, and they can be classified into two types
based on capping. Capping is the first modification
made to RNA polymerase II-transcribed RNA and
takes place co-transcriptionally in the nucleus as
soon as the first 2530 nucleotides are incorporated
into the nascent transcript (Moteki & Price, 2002;
Shatkin & Manley, 2000). Capping ncRNAs include
mRNA-like ncRNAs, characterized by a 7-methyl-
guanosine cap at the 5’ end, enhancing stability for
various cellular functions. Certain small nuclear
RNAs (snRNAs) and small nucleolar RNAs (snoR-
NAs) also undergo capping, facilitating their roles
in pre-mRNA splicing and rRNA modification, re-
On the other hand, uncapped ncRNAs, such
as circRNAs, lack a 5’ cap and form covalently
closed loop structures, often interacting with miR-
NAs. lncRNAs may or may not have a cap, contrib-
uting to their diverse functions in gene regulation
and cellular processes. tRNAs are generally un-
capped, relying on post-transcriptional modifica-
tions for their crucial role in translation (Uppaluri et
al., 2023).
Figure 1: Classification of ncRNAs based on their type, capping, and endogenous functions
Role of ncRNAs in Cancer
Cancer is marked by cells that grow uncon-
trollably, invade other tissues (metastasize), and
lack the capacity to undergo programmed cell death
(apoptosis). Knowledge of the causes and potential
treatments of cancer has increased owing to the dis-
covery of ncRNAs and the advancement of RNA se-
quencing (RNA-seq) technology has made it
Science Reviews - Biology, 2024, 3(1), 1-8 Muhammad Tahir Hayat
possible to investigate the transcriptome of cancer-
ous cells and tissues (Luo, 2016). RNA-seq makes it
possible to determine the frequency and sequences
of dysregulated ncRNAs in cancer (Choudhari et al.,
2020; Luo, 2016). There is substantial evidence that
dysregulated ncRNA expression and downstream
signaling pathways have a direct association with
development and progression of cancer. Figure 2 il-
lustrates the three distinct ways in which ncRNAs
influence cancer progression.
miRNAs have received the greatest research
attention when it comes to the roles played by
ncRNAs in human malignancies (Hayes et al., 2014;
Y. Wang & Lee, 2009). Recent studies have demon-
strated that secreted miRNAs not only cause RNA
interference (RNAi), but may additionally mimic
ligands that trigger prometastatic inflammatory re-
sponses in the microenvironment of the tumor
(Eichmüller et al., 2017).
There is minimal knowledge regarding the
cancer-associated functions of piRNAs. Although
more recent research has looked at the interaction
between PIWI (P-element Induced WImpy testis in
Drosophila) and piRNA in cancers, most of these in-
vestigations to date have focused on the PIWI clade
of Argonaute proteins, including regulatory roles in
stem cell and germ cell differentiation, which oper-
ate independently of piRNAs (Yu et al., 2019; Y.
Zhao et al., 2012). Numerous well-established
lncRNAs (e.g., HOTAIR, H19, MEG3, MALAT1)
have been associated with cancer. They play varied
roles in the development of cancer, particularly in
the areas of drug response, the formation of blood
vessels (angiogenesis), metastasis, cell proliferation,
and post-transcriptional gene regulation. Generally,
the impact of lncRNAs may be classified as either
tumor suppressive or tumorigenic based on the un-
derstanding gained from functional investigations.
However, many lncRNAs may exhibit both de-
pending on the context (Esquela-Kerscher & Slack,
2006; Svoronos et al., 2016).
The number of examples from research on
ncRNAs is far fewer than that of protein-coding
genes, even though genetic changes in genes pro-
ducing ncRNAs have been linked to cancer. One
well-known example is the deletion of the miR-
15/16 tumor suppressors in chronic lymphocytic
leukemia (CLL) at chromosome position 13q14.3
(Calin et al., 2002). Cancer is also related to the am-
plification of chromosomal areas expressing car-
cinogenic ncRNAs, such as FAL1 (Hung et al., 2014)
and PVT1 (Jin et al., 2019). The lncRNAs CCAT2 (B.
Chen, Dragomir, et al., 2020), H19 (Hua et al., 2016),
and ANRIL (Aguilo et al., 2016) are reportedly
linked to the risk of cancer cell proliferation due to
single nucleotide polymorphisms (SNPs).
Apart from the genetic changes inside of tran-
scribed areas, mutated promoters of ncRNAs can
also result in altered levels of gene expression. For
instance, it has been documented that promoters of
the lncRNAs NEAT1 and RMRP undergo frequent
driver mutations in breast cancer (Rheinbay et al.,
2017). In addition to mutations, cancer has also been
linked to ncRNAs producing enzymes, such as
Drosha and Dicer, which are associated with the
processing of miRNA, in addition to abnormalities
in the sequences encoding ncRNA itself
(Rupaimoole & Slack, 2017). Apart from genetic
mechanisms, epigenetic, transcriptional, or post-
transcriptional processes may also result in the up-
or down-regulation of ncRNAs linked to cancer
(Anastasiadou, Faggioni, et al., 2018; Budakoti et al.,
2021; Slack & Chinnaiyan, 2019).
Overall, a range of genetic and epigenetic fac-
tors, such as gene amplification or deletion , repres-
sion of gene transcription , aberrant biosynthesis ,
alternative splicing , and epitranscriptome modifi-
cations or “RNA editing” , including nucleotide
substitutions , methylation , and acetylation , can ac-
count for the dysregulation of ncRNAs in cancers.
Moreover, lncRNAsparticularly circRNAshave
the ability to compete with mRNAs for miRNA
binding sites, such as endogenous RNAs (ceRNAs) .
As a result, miRNAs are unable to carry out their
regulatory functions. For instance, H19 can
"sponge" or lower the availability of let-7 to target
by mRNAs by binding to the sites for let-7 .
Muhammad Tahir Hayat Science Reviews - Biology, 2024, 3(1), 1-8
Figure 2: Noncoding RNAs have three distinct ways for influencing caner progression: they might act as oncogenes, cancer sup-
pressors, or mediators of cancer metastasis. LncRNA H19, miR-21, and miR-17-92 primarily increase the target when utilized as
an oncogene; lncRNA PVT1, miR-372/373, and lncRNA HOTAIR, on the other hand, primarily reduce the target. Both miR-34
and lncRNA MEG3 inhibit tumors, but they also help target P53. Moreover, miR-15a and miR-16-1 impact BCL-2 and prevent
cancer, whereas lncRNA MEG3 influences autophagy and prevents cancer. Long noncoding RNA (lncRNA) affects the target and
hence affects the development of cancer when it prevents tumours from spreading.
Diagnostic and Therapeutic Implications
Research has shown that ncRNAs have utility
in serving as biomarkers for diagnosing cancer and
determining a patient’s prognosis. Biomolecules
linked to ncRNAs can be examined via a liquid bi-
opsy, which is a minimally invasive procedure that
allows for the analysis of biomolecules in the blood,
such as extracellular vesicles (EVs), circulating tu-
mor cells (CTCs), and cell-free DNA (cfDNA).
ncRNAs are stable in blood and their connection to
biomolecules found in the blood can be used an in-
dicator of cancer type and state. For example, cancer
progression and efficacy of therapy are correlated
with expression levels of miRNAs in EVs isolated
from blood samples. Moreover, lncRNAs found in
cfDNA have the ability of distinguishing varieties
of cancer (Chen, Zhang, et al., 2020; Cheng et al.,
2020; Huang et al., 2013; Zhang et al., 2017).
Tissue-based diagnostics performed on tissue
taken from surgeries or biopsies is another way that
ncRNAs are used to diagnose and characterize can-
cer because ncRNAs express themselves differently
in cancerous versus normal tissue. For example,
lncRNAs are dysregulated in several types of cancer,
like HOTAIR in breast cancer and MALAT1 in lung
cancer. Examples of dysregulated miRNAs include
the levels at which miR-21 and miR-155 are ex-
pressed in breast cancer and lymphoma, respec-
tively (Grolmusz et al., 2018; Wang et al., 2017;
Xiong et al., 2019; Zhao et al., 2018).
Beyond their potential for diagnosis, ncRNAs
also have prognostic significance in cancer. Prog-
nostic biomarkers estimate a patient's disease out-
come and the probability of disease progression.
For instance, low expression levels of miR-155 and
miR-21 are correlated with a poor prognosis for
lymphoma and breast cancer, correspondingly.
lncRNAs with a poor prognosis across a variety of
cancer types, such as HULC and HOTAIR, are per-
sistent (Chiu et al., 2018; Liu et al., 2018; Ni et al.,
Despite the potential benefits of ncRNAs for
diagnosis and treatment, ncRNAs in the context of
Science Reviews - Biology, 2024, 3(1), 1-8 Muhammad Tahir Hayat
cancer presents challenges. Functional characteriza-
tion is impeded by intricate and poorly understood
roles and interactions within cellular pathways. Be-
cause of these intricate functions, it is still difficult
to determine the significance of specific ncRNAs in
the initiation and progression of cancer. The high
heterogeneity and contextual dependency of cancer
further complicate ncRNA studies, as their expres-
sion varies based on cancer type, stage, and patient
characteristics. Moreover, identifying and validat-
ing ncRNAs as diagnostic or prognostic biomarkers
is complex, facing challenges such as technical var-
iability and inter-patient variability. Utilizing ther-
apeutic potential encounters hurdles in delivery
and targeting, requiring efficient systems to mini-
mize off-target effects. Regulatory considerations
are crucial for development, requiring adherence to
guidelines and safety assessments. Despite these
challenges, understanding and harnessing ncRNA
potential in cancer holds promise for improved di-
agnostic and therapeutic interventions. However,
obstacles like lack of specificity and limited mecha-
nistic understanding remain significant barriers (Di
Leva & Croce, 2013; Uppaluri et al., 2023).
Conclusion and perspectives
In conclusion, the study of non-coding RNAs
in cancer progression has unveiled a range of regu-
latory mechanisms and potential therapeutic op-
tions. MicroRNAs, due to their precise gene expres-
sion regulation, play a crucial role in coordinating
cellular activities essential for tumor development.
Long non-coding RNAs add complexity to the reg-
ulatory network, influencing various aspects of can-
cer biology as functional modulators and architec-
tural planners. Targeting ncRNAs for therapeutic
purposes shows promise for innovative cancer
treatments, with opportunities for personalized and
targeted interventions through small molecules and
RNA-based therapeutics. However, challenges
such as delivery methods, off-target effects, and un-
derstanding ncRNA interactions must be addressed.
Ongoing research in ncRNAs in cancer biology re-
mains a dynamic field with vast potential. Interdis-
ciplinary collaboration will be crucial to overcome
challenges and translate discoveries from research
to clinical applications.
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