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9 Prostate Cancer andNoncoding RNAs: AFocus onmiRNAs, lncRNAs, andcircRNAs
shown to facilitate the mobility of prostate cancer cells via the direct targeting of
TGF-β induced factor 2 protein (TGIF2) [60]. Additionally, it has been shown that
it involves in prostate cancer cells resistance to docetaxel and cabazitaxel. This
resistance is partially attributed to its ability to modulate p53 phosphorylation and
apoptosis [61]. The miR-93 expression level is seen to be increased in prostate cancer, since it is a constituent of the miR-106b-25 cluster. The involvement of this
factor in the course of diseases is characterized by its ability to upregulate the
expression levels of LATS2, ITGB8, and TGFβR2. Additionally, it has been shown
that miR-93 has a substantial correlation with many clinical indicators in prostate
cancer, including TNM stage, Gleason score, bone metastases, and lymph node
involvement [62, 63].
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9.4 lncRNAs Engagement inProstate Cancer Progression
9.4.1 Oncogenic lncRNAs
The application of quantitative real-time PCR has revealed the upregulation of multiple lncRNAs in prostate cancer tissues when compared to adjacent non-cancerous
tissues or samples of benign prostate hyperplasia (BPH). This observation suggests
that lncRNA transcripts have an oncogenic role in the advancement of prostate cancer. The study of lncRNAs in this area has mostly focused on small nucleolar RNA
host genes (SNHGs). Several carcinogenic lncRNAs, including nuclear paraspeckle
assembly transcript 1 (NEAT1), taurine up-regulated gene 1 (TUG1), plasmacytoma variant translocation 1 (PVT1), metastasis associated lung adenocarcinoma
transcript 1 (MALAT1), differentiation antagonizing non-protein coding rna
(DANCR), and colon cancer associated transcript 1 (CCAT1), have been revealed to
function as oncogenes in prostate cancer, similar to their roles in other types of
cancer. For example, DANCR can develop taxol resistance in this particular kind of
tumor by inuencing the miR-33b-5p/LDHA axis [64]. The expression of lncRNA
has shown an upregulation in blood samples obtained from individuals diagnosed
with prostate cancer, concomitant with a decrease in miR-214-5p. Signicantly,
there exists an association between the DANCR expression and other clinical
parameters such as T stage, Gleason score, and prostate-specic antigen (PSA) level
in the aforementioned patient population. The expression of DANCR has been
shown to have diagnostic signicance in prostate cancer, as well as the ability to
predict poor prognosis in patients with this form of disease. The enhancement of
cell growth and cell migration, prevention of apoptosis, and induction of TGF-β
signaling may be achieved by the increased levels of DANCR or the inhibition of
miR-214-5p expression, as shown by previous research [65]. DANCR has been
shown to have the ability to target miR-185-5p, therefore facilitating the upregulation of LIM and SH3 protein 1, which in turn promotes the progression of prostate
tumors through the PI3K/FAK/GSK3b /AKT/snail axis [66].
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The process of epigenetic suppression of the androgen receptor (AR) corepressor
contributes crucially to the activation of the AR.The regulation of ARLNC1 is likewise inuenced by androgens, leading to an increase in androgen receptor mRNA
stability via its binding to the 3′-UTR.Consistent with this observation, the inhibition of ARLNC1 results in the downregulation of androgen receptor expression and
the repression of AR signaling, ultimately leading to the reduction of prostate cancer development. ARLNC1 plays a signicant role in maintaining a positive feedback loop that triggers and sustains androgen receptor activation throughout the
advancement of prostate cancer [67]. Furthermore, a number of lncRNAs that are
particular to CRPC and controlled by the AR have a signicant role in the upregulation of androgen receptors and their variation. The expression levels of long noncoding RNAs controlled by androgen receptors are shown to be signicantly higher
in tissues of CRPC. The results of the experiment indicate that the reduction of
CRPC tumor development and inhibition of androgen receptor and androgen receptor variant expression may be achieved by the knockdown of (prkag2 antisense
RNA1) PRKAG2-AS1 and hoxc cluster antisense RNA1 (HOXC)-AS1in these
cells. The functional role of PRKAG2-AS1 involves the regulation of the intracellular distribution of the splicing factor u2 small nuclear rna auxiliary factor 2
(U2AF2). The splicing component in U2AF2 has an important role in the AR splicing system [68].
Hox transcript antisense RNA(HOTAIR), a lncRNA, is well recognized as an
androgen receptor-repressed molecule. Its expression is seen to increase during
androgen deprivation therapy (ADT) and in the context of CRPC.In a mechanistic
manner, the lncRNA known as HOTAIR forms a binding relationship with the AR
protein, resulting in the inhibition of its connections with the E3 ubiquitin ligase
mouse double minute 2 (MDM2). Consequently, this inhibition suppresses the process of androgen receptor ubiquitination and subsequent destruction. Consequently,
the HOTAIR molecule stimulates androgen-independent activation of AR and facilitates the transcriptional program regulated by AR in the absence of androgen [69].
Recent research has shown that NEAT1 facilitates the promotion of cancerous
development in prostate tissue by modulating the epigenetic modications in the
promoters of target genes, hence stimulating their transcription [70]. Additionally, it
has been shown that prostate cancer gene expression marker 1 (PCGEM1) and prostate cancer associated non-coding RNA1 (PRNCR1) exhibit binding afnity toward
AR and facilitate the process of selective looping, whereby AR-bound enhancers
are brought into close proximity with target gene promoters [71]. In a similar vein,
it has been shown that the suppressor-of-cytokine-2-antisense RNA1(SOCS2-AS1)
gene interacts with the androgen receptor to facilitate co-factor interaction [72].
Chen and colleagues in their study aimed to examine the involvement of lncRNA
plasmacytoma variant translocation 1 (PVT1) in the pathogenesis of prostate tumor
progression [73]. The ndings of the study reveal that the PVT1 levels are markedly
increased in both prostate cancer tissues and cells. The expression of PVT1 is mechanistically upregulated by the process of METTL3-mediated N6-methyladenosine
(m6A) alterations. Increased levels of PVT1 contribute to the promotion of heightened invasion, migration, and proliferation capabilities in prostate cancer cells,
9 Prostate Cancer andNoncoding RNAs: AFocus onmiRNAs, lncRNAs, andcircRNAs
while a reduction in PVT1 levels leads to contrasting outcomes. Interestingly,
miR- 27b-3p has been recognized as a regulator of both PVT1 and bloom syndrome
protein (BLM). PVT1 functions by sequestering miR-27b-3p, so indirectly facilitating the development of BLM.The research ndings also demonstrate that increased
levels of BLM have a mitigating effect on the negative outcomes of PVT1 knockdown, namely in relation to the migration, proliferation, and invasion of prostate
cancer cells. The cumulative ndings of this study indicate that PVT1 has a role in
promoting the aggressiveness of prostate cancer by inuencing the miR-27b-3p/
BLM axis. These results provide valuable insights into prospective targets for the
development of treatment methods for prostate cancer [73].
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9.4.2 Tumor-Suppressive lncRNAs
Several other lncRNAs have been identied as exerting tumor-suppressive effects in
the context of prostate cancer. For example, it has been shown that the gene
LINC00893 may impede the advancement of this particular kind of cancer by regulating the miR-3173-5p/SOCS3/JAK2/STAT3 axis [74]. In a similar vein, the impact
of LINC01679 on miR-3150a-3p is implicated in the suppression of prostate cancer
advancement via modulating the SLC17A9 transcription [75]. MIR22HG is an
additional lncRNA that functions as a tumor suppressor by serving as a decoy for
miR-9-3p [76]. The involvement of RP1-59D14.5 in prostate tumorigenesis is
attributed to its tumor-suppressor function, which is facilitated by the trigger of the
Hippo signaling pathway and augmentation of autophagy [77]. Furthermore, previous studies have shown that MAGI2-AS3 is a miR-424-5p sponge, leading to the
inhibition of STAT3 signaling and the subsequent suppression of proliferation in
prostate cancer cells [78]. NEAT1-interacting transcriptional repressor (NXTAR) is
an additional lncRNA that regulates the AR expression and inuences enzalutamide
resistance [79]. Indeed, the quantity of discerned tumor-suppressive lncRNAs in the
context of prostate cancer is much lower in comparison to the abundance of oncogenic lncRNAs.
9.4.3 Circular RNAs inProstate Cancer
Circular RNAs, also known as circRNAs, are a category of ncRNA molecules that
possess a covalently closed structure, lacking both 3′ and 5′ ends. The widely used
technique for the discovery of novel circRNAs is high-throughput RNA-sequencing
(RNA-seq), which involves the detection of spliced reads including the backsplicing junctions. After their formation, circRNAs exhibit a remarkable level of
stability owing to their unique circular conformation. Hence, the use of circRNAs
as potential biomarkers in various bodily tissues, blood samples, or urine specimens
has been suggested by Wen’s team study. The precise cellular activities of the
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majority of circRNAs remain elusive [80]. In recent years, research on specic circRNAs has revealed their potential to act as miRNA sponges, interact with RNAbinding proteins to inuence their function, regulate alternative splicing and
transcription, and even undergo translation to generate new bioactive peptides [81,
82]. CircRNAs exhibit abnormal expression patterns in several types of malignant
tumors, including renal cell carcinoma [83], breast [84], and prostate tumors [85].
The dysregulation of circRNAs has been reported in several dimensions of malignant tumor growth, such as tumor development, metastasis, immunosuppression,
and drug resistance [86]. According to Zhang etal. (2019), research conducted on
patient-derived xenograft (PDX) mice models shows that the administration of
intratumor injections of siRNA specically targeting oncogenic circRNA has signicant potential as a treatment strategy for gastric cancer therapy [87]. Furthermore,
it has been shown that circRNAs have potential as reliable indicators for predicting
the prognosis or diagnosing malignant tumors, as evidenced by studies conducted
by recent studies [88, 89]. Both dysregulated and functional circRNAs have signicant contributions in several dimensions of prostate cancer, such as metastasis, cell
cycle, tumor proliferation, invasion, migration, radiosensitivity, and treatment resistance. Certain circRNAs have the capacity to function as valuable biomarkers for
both prognostic and diagnostic purposes.
CircRNAs have a signicant role in the EMT regulation. Yan and coworkers
(2020) conducted an RNA-seq analysis to identify circRNAs associated with EMT
in cells stimulated by interferon-gamma (IFN-γ). Their ndings revealed that hsa_
circ_0001165 and hsa_circ_0001085 have a regulatory function in the EMT process
during prostate tumorigenesis [90]. Feng and colleagues (2019), showed that
circ0005276 molecules facilitated cellular proliferation and EMT via interacting
with FUS [91]. The study conducted by Han and coworkers revealed the downregulation of circSMAD2in prostate cancer tissues. The suppression of the defective
EMT process may be achieved by the restoration of circSMAD2, which in turn
inhibits miR-9 [92]. According to Yang etal., it was said that the regulation of EMT
by p53 occurs via the circAMOTL1L/miR-193a-5p/Pcdha regulatory axis [93].
According to the ndings of Li etal., it was proposed that circ-0016068 can enhance
the EMT in prostate cancer cells via the regulation of the miR-330 3p/BMI-1 axis
[94]. Shen etal. showed that circFoxo3 has inhibitory effects on the cell motility
and invasiveness of prostate cancer cells by modulating the expression of Foxo3 and
EMT [95]. Furthermore, apart from their role in EMT, circRNAs can regulate the
metastatic process of prostate cancer through other mechanisms. In their study, Xu
and coworkers discovered that circRNA-51,217 acts as a sponge for miRNA-646,
resulting in the activation of the TGFb1/p-Smad2/3 signaling and subsequent promotion of prostate cancer cell invasion [96]. According to the ndings of Weng
etal., it has been proposed that the circular RNA_LARP4 has the ability to impede
cell migration and invasion by upregulating the FOXO3A [97]. The study conducted
by Si-Tu and colleagues revealed that circ-102,004 exhibited an oncogenic function
by facilitating the metastasis-related processes in cells of prostate cancer [98]. The
upregulation of circ-102,004 modulates the signaling pathways of Hedgehog,
c-JUNN-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)
9 Prostate Cancer andNoncoding RNAs: AFocus onmiRNAs, lncRNAs, andcircRNAs
193
[98]. It has been shown that circSOBP effectively suppressed the amoeboid migration and metastasis of prostate cancer cells. This inhibitory effect was mediated via
the involvement of the miR-141 3p/MYPT1/p-MLC2 axis [99].
Moreover, recent evidence has shown the engagement of circRNAs in the processes of cell cycle regulation, cell proliferation, and cell death in prostate tumors.
For example, Shan etal. documented that the suppression of circFMN2 resulted in
the inhibition of tumor development invivo and the reduction of proliferation in
prostate cancer cells [100]. This effect was achieved by the cell cycle checkpoint
activation and apoptosis, which was mediated through the regulation of the
miR-1238/LHX2 axis [100]. In their study, Mao etal. found a signicant association between circPDHX and many clinical factors in prostate cancer, including
overall survival, pathological T, stage, and Gleason score. Furthermore, their ndings demonstrated that circPDHX had a role in promoting cell growth in laboratory
settings and tumor progression in animal models [101]. According to Liu etal., it
was proposed that the expression of circHIPK3 was increased in prostate cancer and
that it facilitated the transition from the G2 to the M phase by serving as a miR- 338-3p
sponge [102]. According to Deng etal., the inhibition of circ_0088233 resulted in a
decrease in cellular proliferation and led to G1 phase arrest and cell death by specically inhibiting hsa-miR-185-3p [103]. The suppression of circ_0057553 was
shown to impede cellular viability and promote apoptosis [104]. In addition, it was
proposed that the inhibition of tumor development in animal models and cell cycle
progression in tumor cells might be achieved by the suppression of circABCC4,
which targets the miR-1182-FOXP4 regulatory axis [105].
CircRNAs have been shown to be important for the development of treatment
resistance in several types of cancer. Recent research has examined the involvement
of circRNAs in CRPC.In their study, Cao etal. (2019) applied RNA-seq techniques
to detect a total of 13 circRNAs originating from the androgen receptor gene. This
analysis was conducted on a diverse set of samples, including 47 metastatic CRPC
samples, cell models, and patient-derived xenografts (PDXs), with the additional
utilization of RNase R RNA sequencing. The upregulation of the four most prevalent circRNAs is seen throughout the growth of castration-resistant PDXs, and these
circRNAs may be identied in the plasma of patients diagnosed with prostate cancer [106]. The circRNAs produced from AR have the potential to function as CRPC
biomarkers. In their study, Greene and colleagues discovered that circRNAs exhibited a higher frequency of downregulation in prostate cancer cells that were resistant
to enzalutamide. This nding was obtained by the use of a high-throughput circRNA microarray [107]. Hsa_circ_0004870, a circRNA that was shown to be
decreased, has been implicated in potentially facilitating the progression of enzalutamide resistance in prostate cancer. Wu and coworkers (2019) showed that the circRNA17 expression was much lower in enzalutamide-resistant cell lines derived
from CRPC C4–2 cells, in comparison to the parental sensitive cells. This study
proposes that circRNA17 may regulate the sensitivity of cells to enzalutamide by
means of the miR-181c-5p/ARv7 axis [108]. Xiang etal. (2019) indicated that circUCK2 expression was reduced in cells that had developed resistance to
194
enzalutamide. The potential therapeutic efcacy of targeting these circRNAs might
be important in the development of novel treatment strategies for CRPC [109].
Docetaxel is the rst chemotherapeutic medication that has been substantiated to
effectively extend the life duration of individuals diagnosed with metastatic
CRPC.The ndings of the STAMPEDE study support the recommendation for the
rst administration of docetaxel in individuals diagnosed with metastatic hormonenaive prostate cancer. Recent research has shown that circRNAs have a role in the
susceptibility of prostate cancer to docetaxel. Shen etal. (2020) proposed that the
downregulation of circFoxo3 contributed to an increase in chemoresistance to
docetaxel in prostate cancer patients. The siRNAs utilized to deplete circFoxo3
resulted in the promotion of docetaxel resistance in mice xenografts. Conversely,
the administration of circFoxo3 led to an extension in the survival of animals with
tumors and an augmentation in the sensitivity to docetaxel [94]. According to the
ndings of Gao etal. (2020), it was demonstrated that the hsa_circ_0000735 expression was increased in prostate cancer tissues that were resistant to docetaxel treatment. Moreover, this upregulation was found to be associated with a worse overall
survival outcome. The downregulation of hsa_circ_0000735 resulted in increased
responsiveness of prostate cancer cells to docetaxel treatment and reduced cell viability in an invivo setting. Furthermore, the suppression of hsa_circ_0000735 was
shown to enhance the sensitivity to docetaxel and inhibit tumor development invivo
[110]. A study conducted by Zhang’s team demonstrated that the exosomal circXIAP molecule had an important role in the docetaxel resistance development in
prostate cancer by modulating the miR-1182/TPD52 axis [111].
A. Nazari et al.
9.4.4 Discussion andPotential ofncRNAs inProstate Cancer
Diagnosis andTreatment
Numerous ncRNAs have a pivotal role in the prostate cancer progression through
inuencing and regulating androgen receptor signaling, the degradation process of
androgen receptors via ubiquitin-proteasome mechanisms, or other critical signaling pathways. Certain biomarkers, such as lncRNA-PCA3, have a high degree of
specicity toward prostate cancer, making them suitable for diagnostic purposes.
Various tumors have differential expression levels of certain genes, which may
either be overexpressed or under-expressed. These genes have the potential to serve
as therapeutic targets for a diverse array of human malignancies. The disparities in
the expression of certain ncRNAs between CRPC and cases that respond to androgen deprivation therapy suggest that these transcripts participate crucially in determining patients’ response to this therapy approach. Moreover, these transcripts can
be considered as potential targets for addressing resistance to this therapy.
While a considerable number of ncRNAs unique to prostate cancer or related to
prostate cancer have been identied, only a limited number of these ncRNAs have
been validated in separate groups of patients or authorized for clinical use. One of
9 Prostate Cancer andNoncoding RNAs: AFocus onmiRNAs, lncRNAs, andcircRNAs
195
the signicant advancements in the domain of lncRNA investigation is perhaps the
endorsement of urine lncRNA-PCA3 as an indicator for the identication of prostate cancer by the FDA [112]. PCA3 has signicant potential as a biomarker for
prostate cancer diagnosis by urine testing, demonstrating a more effective performance when compared to prostate-specic antigen (PSA) in the urinary identication of this condition. Additional research is required to identify other lncRNA
biomarkers that are suitable for this particular kind of cancer. LncRNAs proles
have the potential to be used for the identication of prostate cancer patients who
may get therapeutic benets from radiation. For example, it has been shown that
UCA1 has a role in modulating the susceptibility of prostate cancer cell lines to
radiation, suggesting its potential as a biomarker for anticipating the effectiveness
of radiotherapy in this patient population. The impact of UCA1 on radiosensitivity
is mediated via its inuence on the course of the cell cycle [113]. The signicance
of ncRNAs in regulating cellular processes such as cell metastasis, invasiveness,
and proliferation has positioned them as promising targets for therapeutic interventions in prostate cancer. The ndings from animal research have shown considerable
potential, especially in relation to some non-coding RNAs that are controlled by
androgen receptors. It is worth noting that non-coding RNAs also have a role in the
development of drug resistance in prostate cancer cells, making them suitable candidates for therapeutic intervention [114]. As an example, the upregulation of
HORAS5 has the potential to induce taxane resistance in CRPC cells by upregulating BCL2A1. The silencing of HORAS5 has been shown to decrease the cabazitaxel resistance of prostate cancer cells, hence improving the effectiveness of
chemotherapy [115].
The involvement of signaling pathways in prostate cancer including STAT3, p53,
PI3K/AKT/mTOR, TGF-β, Wnt/β-catenin, FAK/AKT/β-catenin, FAK/PI3K/AKT/
GSK3b/Snail, NF-κB, FOXO, and Ras/ERK signaling pathways, has been extensively covered in previous chapters. These signaling pathways, which are subject to
modulation by ncRNAs, are also relevant regarding prostate cancer. Furthermore,
numerous diverse ncRNAs exhibit intercommunication with one another. For example, it has been shown that some lncRNAs or circRNAs function as molecular
decoys, effectively sequestering miRNAs and therefore modulating the expression
of target miRNAs.
While the expression prole of ncRNAs has been extensively evaluated in
tumoral tissues of individuals diagnosed with prostate cancer, there has been a relatively limited focus on the investigation of their levels in serum or urine samples.
Given the accessibility of these resources for non-invasive diagnostic tests, it is
recommended that future research concentrate on these biological uids in order to
enhance the early identication of prostate cancer using non-invasive means.
Collectively, ncRNAs have a considerable role in the tumorigenesis of prostate cancer in many ways. The aforementioned transcripts have the potential to act as viable
subjects for targeted therapy in the context of this particular malignancy.
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