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Asian Journal of Research in Medicine and Medical Science
4(1): 40-50, 2022; Article no.AJRMMS.797
Investigation of Research Progress and the
Emerging role of Circular RNA in Lung Cancer
Kodagoda Thudugalage Nimalsha Hansani a* and Hashani Vithanage a
a Department of Physiology and Human Biology, VNU University of Science, Hanoi, Vietnam.
Authors’ contributions
This work was carried out in collaboration between both authors. Author KTNH designed the study,
performed the statistical analysis, wrote the protocol and first draft of manuscript. Author HV manage
the analyses of the study and literatures researches. Both authors read and approved the final
manuscript.
Received 22 December 2021
Accepted 27 February 2022
Published 28 February 2022
ABSTRACT
Lung cancer is identified as the leading cause of cancer-related deaths globally, with a 5-year
survival rate [1]. More than 85% of lung cancer cases are related to non-small cell lung cancer
(NSCLC).The number of lung cancer cases is increasing every year globally. The development of
lung cancer targeted therapies has shown significant improvement for the diagnosis and treatment
of lung cancer but in spite of developing results with the targeted therapies, the early diagnosis and
therapy of lung cancer still remain dismal. CircRNAs are a class of non-coding RNA with
endogenous single-stranded covalently closed structures with tissue-specific and cell-specific
patterns. CircRNAs generally originate from pre-mRNA undergoing non-canonical back splicing.
After that, using next-generation sequencing (NGS) and data from bioinformatics, it was clarified that
circular RNA has a high diversity and has relationship with cancer, and circRNAs are involved in the
occurrence of various diseases. The expression level of the circRNA is varied across tissues, cell
types, blood, and serum, aberrantly causing the various levels of expression of cancers. Based on
the studies, this review discusses circRNA for the progression of lung cancer, the relationship
between circular RNA and various types of cancers, including their biogenesis and functions, their
sorting mechanisms, their potential roles for promoting and inhibiting cancer, and the emphasis on
demonstrating whether circRNAs can be potential biomarkers for the prognosis and diagnosis of
cancer.
Keywords: Lung cancer; circular RNA; microRNA sponges; biomarkers; therapeutics; non-small cell
lung cancer.
ABBREVIATION
LC : Lung cancer
NSCLC : Non-small cell lung cancer
SCLC : Small cell lung cancer
CircRNA : Circular RNA
LUSC : Squamous cell carcinoma
LUAD : Lung Adenocarcinoma
Review Article
Thudugalage et al.; AJRMMS, 4(1): 40-50, 2022; Article no.AJRMMS.797
41
ecirRNA : Exonic circular RNA
ciRNA : Circular intron RNA
eicirRNA : Exon intron circular RNA
siRNA : Short interfering RNA
NGS : Next-generation sequencing
RBP : Ribosome binding proteins
MBL : Muscle blind
IRES : Internal ribosome binding site
ORF : Open reading frame
miR-7 : miRNA 7
TNM : Tumor node metastasis
LNM : Lymph node metastasis
EGFR : Epidermal growth factor receptor
PDTX : Patient-derived tumor xenografts
AON : Antisense oligonucleotide
1. INTRODUCTION
Lung cancer (LC) has continually remained the
leading cause of cancer with the highest
mortality rate globally, and it’s a commonly
diagnosed cancer type worldwide [1]. In 2021,
approximately 2.21 million lung cancer cases
were reported, with 1.80 million deaths
representing all cancer-related deaths worldwide
[2]. The most prevalent types of lung cancers are
non-small lung cancer which account for
approximately 85% of all lung cancers, mainly
including adenocarcinoma (LUAD) and
squamous cell carcinoma (LUSC) [3]. Moreover,
researchers have demonstrated the disease
mechanisms, linking lung tumorigenesis like
EGFR or KRAS, and also indicated the
phenomenon rates and disease development [4].
But these underlying mechanisms remain
unknown and contribute to advances in disease
pathogenesis. It is the major key for developing
new strategies for specific types of diseases
diagnosis, prognostic and therapeutic tools for
lung cancer.
As a consequence of high stability, circular RNA
is a relevant family of non-coding RNA which is a
closed circular structure formed by covalent
bonding without a 3’-poly-A tail and a 5’-
methylated cap. It makes them more stable in
tissues and plasma [5]. Furthermore, circular
RNA forms from non-canonical back splicing of
primary transcripts of mRNA where an upstream
5’ splice acceptor is joined to a downstream 3’
splice donor. Based on their circular structure,
circRNAs are more stable and resistant to RNA
degrading endonucleases [4,5]. It has been
reported that circular RNA can function as
miRNA sponges to regulate gene expression
and act as promising disease biomarkers.
Because it has a much longer circulatory half-life
compared with linear RNA [2]. According to next-
generation sequencing, especially high-
throughput RNA sequencing and bioinformatics
tools, numerous circular RNAs are recognized,
and it has disclosed the great abundance and
dysregulation of diverse circular RNA in various
types of diseases, illustrating their involvement in
disease development and its progression. Owing
to the high stability of blood and other additional
body fluids, circular RNA is considered a
potential biomarker for cancer risk prediction [6].
Furthermore, circular RNA acts as potential
target for the diagnosis and prognosis of various
types of cancers and is considered a promising
novel biomarker of cancer. This review focuses
on the understanding of circular RNA and its
involvement in cancer progression, emphasizing
the significant aspects of circRNAs in cancer
development, which can provide novel strategies
for potential clinical applications [6].
2. HISTORY OF CIRCRNAS
In 1976, Sanger et al. identified the circular RNA
(circRNAs) in pathogens such as viroids,
including the plant virus types [7]. It is proven
due to its circular structure and values of
biochemical analysis. It is caused by the
experimental interference predictions that form
the erroneous exon transcripts [4,7].
Furthermore, recent research, high-throughput
sequencing, and bioinformatics tools show that
circRNAs are not the result of incorrect splicing
of pre-mRNAs but are biologically stable and
expressed with greater diversity in human cells.
These circRNAs are revealed to have different
mechanisms for each type of disease in humans.
Some increased studies are proof that the
circRNA are expressed in divergence and act as
a significant regular element in the
carcinogenesis and progression of lung cancer
[8].
2.1 Classification and Characteristics of
circRNAs
Most circular RNA is stably expressed in protein-
coding genes consisting of single exons or
multiple exons that result from alternative
splicing of circular RNA. Based on their different
structures and their origins, circular RNA can be
categorized into 3 main groups, such as exonic
circular RNA (ecircRNA), circular intron RNA
(CiRNA), and exon-intron circular RNA
(EIcircRNA) [9]. ECircRNA is considered the
largest subclass of circRNA that comprises
approximately 85% of circRNA [1], including only
Thudugalage et al.; AJRMMS, 4(1): 40-50, 2022; Article no.AJRMMS.797
42
exons, which can be one or more. Some reports
suggest that circRNAs are predominantly located
in the cytoplasm and function to enhance levels
of microRNA target genes through the
adsorption of microRNA molecules.
CiRNA consists of a 3’-5’ or 2’-5’ phosphodiester
bond and mainly resides in the nucleus,
regulates the gene transcription of their parental
mRNA [4,5], and increases the parent gene
expression. In this case, CiRNA contains only
introns. EIciRNA shares some characteristics
with the circRNA and CiRNA. As EIcircRNA is
composed of both exons and introns in its
structure, circRNAs, which are predominantly
located in nucleus, regulate the expression of
parental genes in the nucleus via interaction with
the U1 small nuclear ribonucleoprotein (snRNP).
2.2 Biogenesis of circRNAs
Focusing on the biogenesis of the circRNAs,
pre-mRNAs are the primary product of the
transcription, undergoing either canonical
splicing or back splicing. As a result, circRNAs
are principally generated through non-canonical
back splicing of the mRNA that is activated by
the spliceosome machinery to remove the
introns from the linear mRNA. Furthermore, back
splicing is a spliceosome-mediated process that
involves the joining of a downstream 5’ splice
site of an exon to an upstream 3’ splice site of
another exon to form the circRNA [4].
The biogenesis of the circRNAs is mainly
regulated by 3 different models of lariat-driven
circularization, intron pairing circularization, and
RNA binding proteins-mediated driven
circularization [1]. The circRNAs are the most
abundant type of circRNA that can be formed by
applying the three main models of driven
mechanisms. The two main mechanisms, such
as direct back splicing and exon skipping, are
utilized in these models. In the lariat-driven
circularization model, a downstream 5’ splice site
of an exon is joined with an upstream 3’ splice
site, resulting in the exon-skipping and the
formation of the lariat, which consists of exons
and introns [5].
Moreover, introns are removed from these lariats
to generate the EIcircRNA. In addition, an intron
pairing-driven mechanism is used for the
formation of the circular RNA with the introns
that are called the EIcircRNA. In this
mechanism, it depends on the conserved motifs
at the ends of both introns. These considered
motifs can prevent the intron’s debranching and
circular form with a 3’5 or 2’5 phosphodiester
bond between the splicing donor and branch
point [10].
Fig. 1. This is an illustration of the biogenesis of circRNA. Zhang, C., Ma, L., Niu, Y., Wang, Z.,
& Xu, X. (2020). Circular RNA in Lung Cancer Research: Biogenesis, Functions, and Role (Y.
LI, Ed.). International Journal of Biological Sciences, 16(5), 803-814.
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43
2.3 Functions of circRNAs
The functional mechanism of the circular RNA is
different in human cells, such as acting as the
miRNA sponges, interaction with RBPs,
regulation of gene transcription, and translation
of proteins. According to the functional value of
circular RNAs (circRNAs), it can be classified
into two types of categories, including those
involving the regulation of its hosting genes and
targets of different genes [4].
2.4 CircRNAS as miRNA Sponges
CircRNAs are identified as stable in the cell as
they lack a 5'end and poly-A tail, which have the
capability of preventing ribonuclease
degradation [11]. Furthermore, the miRNA
sponges act as the competitive inhibitors that
suppress the miRNAs binding to mRNA targets
[5]. These circRNAs are natural miRNA
sponges. Moreover, miRNA are the dominant
genes for expression regulators that bind to
specific sites of mRNA to prevent its translation
or promote its degradation. Memczak et. al and
Hansen et al. were demonstrated that the
CDR1as contains the single exons, it can
suppress the activity of the miR-7, it suggests
that it can be bound densely into this target
miRNA that it can be upregulated the expression
of miR-7 targets such as SNCA, EGF, and IRS2.
Some researchers indicated that ciRS-7 consists
of more than 70 selective binding sites to miR-7
and its ability to bind for miR-7 are 10 times
higher than other known transcripts.
2.5 Interaction with RBPs
As a functional value of circRNAs, they can bind
with the RBPs and function as RBP sponges.
Many circRNAs can interact with proteins, and
this affects the functions of proteins. circMBL
can be identified as the first circRNA acting as
the protein sponges that originated from the
exons of the gene encoding muscle blind.
However, this circMBL has putative multiple
binding sites that are shown for some MBLs,
which are facilitated for circularization of circMBI
by the second exon of the MBL gene.
Nevertheless, this overexpression of MBL is
capable of diminishing the production of linear
mRNA by increasing the production of circRNAs.
Circ-FOXO3 is identified as another well-
distinguished type of circRNA molecule that
serves as a protein scaffold. The different levels
of circ-FOXO3 have been shown to increase in
the heart tissue of old patients and decrease in
several types of cancer tissues. And circ-FOXO3
plays a vital role in apoptosis, which is inhibited
by the MDM2 (murine double minute 2 protein).
Moreover, circ-FOXO3 acts as the protein
scaffold to bind p53 and MDM2, which promotes
the combination of p353 and MDM3 to
accelerate p53 degradation [6]. In addition to
that, these RBPs are involved in almost all
cellular processes, such as apoptosis,
proliferation, and differentiation [11].
2.6 Regulation of gene expression
On the contrary, to eciRNAs, ciRNAs, and
EIciRNAs, play a crucial role in gene expression
in the cell, they have gathered in the nucleus
and have functional value at the transcriptional
level. In fact, types of EIciRNAs are recognized
as circEIF3J and circPAIP2 that can interact with
the U1 small ribonucleoproteins. Subsequently, it
increases the host gene transcription by binding
with RNA polymerase. It is caused by parental
gene transcription. The cis and trans-acting
factors are involved in parental gene expression
at the transcription level that is localized in the
nucleus for specific circRNAs.
2.7 Translation of circRNAs
CircRNAS are identified as a type of ncRNA as
there is insufficient proof of their translation
mechanisms. But researchers are currently
carrying on studies about the translational
capacity of circRNAs. Due to the lack of a 5'-
methylated cap and a 3’-poly-A tail, circRNA
shows cap-independent translation mechanisms
[12]. It is mediated by N6-methyladenosine
(m6A), a type of ORF (open reading frames),
and IRES elements (internal ribosome entry
site). CircRNAs appeared to reveal the major
vital function for 50 end-independent
translations. Despite a strong impact on the
translational control mechanisms through their
sponge function and constituting the new mRNA
family, the proteins for their pathophysiological
roles are not translated. Using the high-
throughput analysis data, circ-ZNF609 is
identified as the ORF that can be translated for
the splicing-dependent and cap-independent
translation mechanism. Recent studies have
revealed that a list of circRNAs in Drosophila has
functional value for translation mechanisms, and
this N6-methyladenosine (m6A) is enriched in
many circRNAs. The recognition protein named
YTHDF3 can bind to the modification sites of
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44
circRNAs to enlist the translation initiation factors
eIF4G2 and eIF3A to start the translation of
circRNAs in the cap-independent translation
mechanisms. Studies indicate that 16% of
human circRNA can encode for proteins that
differ from the host genes, but it is homologous
for other proteins [6,11].
2.8 circRNAs in Lung Cancer
CircRNAs play a vital role in the development of
human diseases, and their potential prognosis,
diagnosis, and therapeutic values are developing
for further studies. In spite of the finding of a
large number of circRNAs in lung cancer tissues
and their cell lines, many circRNAs are identified
to be abnormally expressed in lung cancer
patients. CircRNAs can regulate lung cancer cell
proliferation, migration, and invasion in their
tissues [3]. Wan et al. revealed that the level of
expression of cir-ITCH can be decreased in lung
cancer cell lines and that this cir-ITCH acts as
the miR-7 and miR-214 sponge in lung cancer,
raising the expression of parental tumor
suppressor genes and blocking the activation of
the Wnt/β-catenin signaling pathway [13].
Via the Wnt/β-catenin signaling pathway,
circRNAs can promote or inhibit lung cancer cell
proliferation, migration, and invasion via the
Wnt/β-catenin signaling pathway. CircRNA is
overexpressed in lung cancer cells and tissues,
resulting in cancer progression [5]. An instance
of Liu et al. showed that circ_007142, miR-186,
and FOXK1 activated the Wnt/β-catenin
signaling pathway for LUAD cell progression.
Ding et al. indicated that circ_001569 regulated
the Wnt/β-catenin signaling pathway to promote
cell proliferation in LUAD cells, raising the
circ_001569 expression shown in the poor
survival proofs. In addition to that, several
functions of circRNAs for lung cancer are
mediated by the Wnt canonical pathway. For
example, circ-SOX4 plays a vital role via miR-
1270/PLAGL2 in activating the signaling
pathway for the WNT in LUAD cells. However,
some circRNAs are downregulated in NSCLC,
providing a resistance role for lung cancer
progression through the inactivation of the Wnt
canonical pathway.
Hansen et al. indicated that CDR1 plays a great
role in tumor-suppressing by sponging a large
amount of miR-7, although miR-617 can bind
with CDR1 to increase the cleavage and release
miR-7 [14]. MA et al. suggested that circMANB2
can promote the expression patterns of FOXK1
via sponging miR-1275, which speeds up cell
proliferation and invasion in cancer progression.
Moreover, Jiang et al. demonstrated that
hsa_circ_007385 is closely associated with cell
proliferation, invasion, and metastasis and is
related to miR-181. And, some other researchers
named Yin et al. highlighted that circUBAP2
plays an important role in the cell proliferation
and invasion of lung cancer cells and it shows a
specific mechanism that is related to miR-339-
5p, and miR-96-3p [15,16]. Moreover, circRNA
100146 acts as the oncogene in NSCLC by
iterating the splicing factors SF3 family and
binding with miR-361-3p and miR-615-5p to
regulate the downstream mRNA. Researchers
have recognized the significance of circRNAs in
modifying their stable expression and presenting
them in relatively high quantity in the human
blood. However, circRNA-100876 can regulate
MMP-13 expression via sponge function, altering
tumor proliferation, and metastasis [17]. In
addition, Zhu et al. demonstrated that
hsa_circ_0013958 is upregulated on the
oncogene cyclin D1, Which promotes cell
proliferation, invasion, and inhibits cell apoptosis.
The level of hsa_circ_0013958 is associated
with the TNM stage and lymphatic metastasis
[18]. In addition to that, the mutation in the genes
is caused by the production of the circRNA,
which is closely associated with the occurrence
of lung cancer and shows the role of the
genetics of lung cancer.
CircRNA acts as a prognostic, and diagnostic
biomarker and is used as a therapeutic target.
The mechanism underpinning the progression of
the disease is not yet completely elucidated, but
the disease pathogenesis is prominent for
developing new strategies towards the disease's
diagnosis and target therapies. Traditional blood
markers such as neuron-specific enolase (NSE),
progastrin-releasing peptide (pro-GRP), and
carcinoembryonic antigen (CEA) are used as
indicators for a biological and pathological
process for measuring and evaluating the
circRNA involvement in lung cancer [5]. The
higher number of circRNA shows aberrant
expression in human peripheral blood and
tissue, collected from lung cancer patients [5].
As a result of pathological processes, circRNA
shows different patterns of expression. It
demonstrates that circRNA can be used as a
potential biomarker in lung cancer.
2.9 Prognostic Potential of circRNAs in
Lung Cancer
CircRNAs showed different patterns of
expression levels in lung cancer, and it is crucial
Thudugalage et al.; AJRMMS, 4(1): 40-50, 2022; Article no.AJRMMS.797
45
for evaluating the prognosis of lung cancer as a
biomarker of circRNAs [19]. These expression
levels are associated with the stage and
prognosis of the disease and are extensively
related to the clinical features of lung cancer
patients. It is identified as the new prognostic
biomarker in clinical features, and circRNA is
considered to have the same prognostic values
as the biomarker in lung cancer. In this case,
some studies have revealed that
hsa_circ_100395 expression is found in lower
amounts in patients with advanced TNM stage.
Ying et al. highlighted that the circ-TSPAN4
expression level is higher in LUAD tissue and its
cell lines, mentioning that it is used as a
promising prognostic biomarker for LUAD
patients [20]. Furthermore, many circRNAs have
a higher expression level in NSCLC tissue
samples, which is related to the TNM stage and
lymph node metastasis. For example, Zhang et
al. demonstrated that circRNA CDR1as is
upregulated in NSCLC tissues and that patients
with high circRNA CDR1as levels had a shorter
OS [21]. Circular BTG3-associated nuclear
protein (Circ-BANP) is upregulated in lung
cancer tissues and cell lines and is higher in
stage III-IV cancer. The higher expressions of
circ-BANP are closely related to the decreased
OS based on the results of the Kaplan-Meier
curve analysis [22]. Based on these studies,
circRNA can be used as a diagnosis,
therapeutic, and prognostic tool for lung cancer
patients.
When serum FCER1 levels in SCLC patients
were compared to normal controls, Li et al.
discovered that FECR1 expression was higher in
SCLC patients and much higher in distant
metastasis. And this expression level of FCER1
is closely associated with the chemoresistance
of SCLC patients. Serum EFCR1 is important for
detecting and tracking SCLC.
Hsa_circRNA_103827 was highly expressed in
the lung squamous cell carcinoma patients and
hsa_cicrcRNA_000122 was low in expression in
the patients [17]. Their level of expression is
closely associated with the survival rate of the
patients. In addition to that, lung cancer has
extremely high malignancy tumor cells, and it is
very effective the analyzing the prolonged
survival of lung cancer patients. It is a fact that
abnormal expression of circRNA can affect for
prognosis of lung cancer. The expression of
circRNA_100876 was elevated in NSCLC
tissues in samples, and higher expression of
circRNA_100876 was associated with LNM and
advanced tumor staging in NSCLC. Additionally,
an increased level of expression of
circRNA_100876 correlates with a short OS time
in NSCLC patients. These significant findings
indicate that circRNA_100876 is associated with
the carcinogenesis of NSCLC. It could be used
as a prognostic biomarker and therapeutic target
for NSCLC.
2.10 Diagnostic Potential of circRNAs in
Lung Cancer
The diagnostic values of circRNAs can be
detected in human plasma as cancer cells enter
the blood circulation. It can be used to determine
if patients with lung cancer are healthy people
[19]. CircRNAs show a higher tolerance to RNA
exonuclease because of their covalently closed
structure. It functions as a diagnostic biomarker
due to its stable structure, higher abundance,
and tissue-specific expression.
For instance, Zhu et al. indicated that
hsa_circ_0013958 was upregulated in patients’
LUAD tissues and plasma. And these levels of
hsa_circ_0013958 were closely associated with
lymphatic metastasis. However, plasma
hsa_circ_0013958 determined the LUAD cases
from its healthy control system [23]. These
studies demonstrated that eh hsa_circ_0013958
can be used as non-invasive biomarkers for
LUAD patients with high sensitivity and
specificity [23]. Based on the research of the
development of circRNA studies, circRNA can
be used as a clinically recognized biomarker for
the diagnosis of early stages of lung cancer.
Circ-ITCH can sponge miR-7 and miR-214. It
can inhibit the activation of the Wnt/β-catenin
pathway in lung cancer patients. Moreover, it
can regulate lung cancer cell proliferation [21].
Circ-ITCH is identified as the epigenetic miRNA
sponge that can increase ITCH expression.
However, Circ ITCH can act as a tumor
suppressor gene in lung cancer as it can control
miRNA activity. It shows that circ- ITCH is
important for the diagnosis and target therapies
for cancer. The expression level of
hsa_circ_0014130 is closely related to the
Tumor Node Metastasis (TNM) lymphatic
metastasis of NSCLC and ROC (Receiver
operating characteristics ) curves were utilized to
distinguish the diagnostic potential of
hsa_circ_0014130 [24].
2.11 circRNAs May Serve as the
Therapeutic Targets in Lung Cancer
Various approaches have been developed to
study the mechanisms of circRNAs and their
Thudugalage et al.; AJRMMS, 4(1): 40-50, 2022; Article no.AJRMMS.797
46
target therapies for therapeutic purposes. There
are some strategies used to overexpress
circRNAs and develop their strategies for
therapeutic potential. Due to their circular
structure [25], circRNAs are stably expressed in
the cell, tissues, and plasma. Several circRNAs
are involved in the tumorigenesis and
progression of NSCLC, acting as potential
therapeutic tools for the treatment of lung
cancer. We can recognize some strategies such
as RNA interference-mediated circRNA
knockdown, circRNAs expression vectors,
synthetic circRNAs, and exosome delivery of
therapeutic tools [26].
RNA interference mediates circRNA knockdown.
It is involved in the sequence-specific
suppression of gene expression and takes
advantage of the endogenous RNAi mechanism
through double-stranded RNA molecules [26].
These knockdowns of circRNAs are generally
mediated by short interfering RNA (siRNA) that
targets the circRNAs by complementary pairing
and integrates from into the RNA-induced
silencing complex. In fact, during the knockdown
process of circRNA with support of
corresponding linear mRNA, the back splice
junction of circRNA is normally targeted, and
antisense oligonucleotide (AON) can also target
circRNAs via complementary pairing. Because of
its long length, normally it is not used as the
target back-splice junction to knock down the
circRNAs but efficiently blocks the protein
interaction placed on the circRNAs. There are
some limitations in RNAi molecules, such as
rapid degradation by nuclease, intracellular
delivery efficacy, and lack of cell specificity, that
affect their ability to act as therapeutic tools for
lung cancer. CircPRKCI is formed from the
PRKCI gene, acts as a tumor-promoting factor
for lung adenocarcinoma (LAD), and is related to
the T-stage and TNM stage patients of LAD.
This knockdown of circPRKCI causes a
decrease in the tumor size and tumor weight.
However, patient-derived tumor xenografts
(PDTXs) have been identified as the translation.
Fig. 2. This table demonstrates the prognostic and diagnostic value of lung cancer.
Chen, H.-H., Zhang, T.-N., Wu, Q.-J., Huang, X., & Zhao, Y. (1-21). Circular RNAs in Lung
Cancer: Recent Advances and Future Perspectives. Frontiers in Oncology, 11(July)
Thudugalage et al.; AJRMMS, 4(1): 40-50, 2022; Article no.AJRMMS.797
47
models and intra-tumoral injection of cholesterol
conjugated si-circPRKCI can be utilized to show
the therapeutic potential of circPRKCI. This great
finding indicates that the growth of PDTX is
decreased in the si-circPRKCI group, resulting in
the therapeutic potential of circPRKCI [27].
Moreover, circRNAs are crucial for drug
resistance in lung cancer. Tumors can develop
drug resistance during the early and late phases
of drug treatment. This drug resistance can be
classified into two therapeutic categories, such
as primary and secondary resistance. The
Thr790Met mutation in the epidermal growth
factor receptor (EGFR) can increase the
resistance to tyrosine kinase inhibitors.
Moreover, tumor reprogramming of the lung
microenvironment can induce resistance to
angiogenesis and immune molecular target
therapies for lung cancer.
Generally, circRNAs are produced from back
splicing that can be driven by the paring of
intronic complementary flanking sequences of
exons and RBPs. This mechanism is designed
by the circRNA vectors as the standard method
of circRNA overexpression [28-46].
3. CONCLUSION
RNA- seq technologies are involved for the
outstanding perception into the human genome,
clinical values, and various diseases including
lung cancer. Because these circRNAs have
participated in cell proliferation, invasion,
metastasis, cell apoptosis and act as well-
recognized biomarkers for therapeutics tools.
Some clinical facts are related to providing
evidence for the success of these molecules as
biomarkers such as the function of circRNAS in
lung cancer is of the little known range, more
studies are required to understand and research
on the tumor microenvironment, heterogeneity.
More research is carried out on the
understanding of the different pathological
processes of circRNA in lung cancer. And
clinical trials were conducted to confirm these
biomarkers used as the therapeutic tools for lung
cancer. Due to the great process of target
therapy, immunotherapy has provided hope for
lung cancer patients, emerging that issues of
drug resistance are mandatory for new
approaches to early diagnosis and treatment of
lung cancer. These reveals are proven that
circRNAS are widespread in research to study
more advances in the relationship with lung
cancer. But current knowledge of circRNA and
its roles in lung cancer is limited and continuous
studies will help to get closer to new knowledge
of circRNA that can be effectively used for lung
cancer treatments.
FUNDING AND GUIDANCE
I am sincerely grateful to VNU University of
science for their kind assistance.
ACKNOWLEDGMENTS
I would like to thank Dr. Tulinh Nguyen for
guidance in studying the circRNA pathway and
lung cancer.
COMPETING INTERESTS
Authors have declared that no competing
interests exist.
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