Submitted - October 18, 2024 | Revised December 4, 2024 Accepted - December 7, 2024 | | ePublished - December 31, 2024
https://doi.org/10.52733/KCJ22n4-r1
ABSTRACT
BACKGROUND: Renal cell carcinoma (RCC) is the most common
kidney malignancy, often associated with poor prognosis due to
late-stage diagnosis and metastasis. Recent research has identified
PIWI-interacting RNAs (piRNAs) and PIWI-like proteins as
potential biomarkers and therapeutic targets in cancer, including
RCC. This systematic review aims to evaluate the role of piRNAs
and PIWI-like proteins in RCC pathogenesis, prognosis, and
treatment.
METHODS: A systematic search of PubMed and ScienceDirect
databases from 2014 to 2024 was conducted according to PRISMA
guidelines. Eligible studies included randomized controlled trials,
cohort studies, and case-control studies investigating piRNAs and
PIWI-like proteins in RCC. A total of 13 studies were included,
with the quality of studies assessed using the Newcastle-Ottawa
Scale.
RESULTS: Several piRNAs, such as piR-1742, piR-31115, and
piR-57125, were found to be dysregulated in RCC, contributing
to tumor proliferation, invasion, and metastasis through pathways
like PI3K/AKT and epithelial-mesenchymal transition (EMT).
PIWI-like proteins, particularly Piwi-like 1, were associated with
advanced tumor stages and poor survival outcomes, making them
significant prognostic markers. Mitochondrial piRNAs, including
piR-34536 and piR-51810, were identified as novel biomarkers
for RCC prognosis.
CONCLUSION: piRNAs and PIWI-like proteins show great
promise as emerging diagnostic and prognostic biomarkers, as
well as therapeutic targets in RCC. While these molecules have
demonstrated potential in RCC management, further research
is needed to confirm their clinical relevance and mechanisms of
action. Future studies should focus on larger, well-structured
cohorts to validate these findings and explore therapeutic
interventions targeting piRNAs and PIWI-like proteins.
INTRODUCTION
Renal cell carcinoma (RCC) is the
most common form of kidney
cancer, representing approximately
3% of all adult malignancies
and posing significant clinical challenges
due to late-stage diagnosis and
high rates of metastasis.1-5 The clear
cell subtype (ccRCC) accounts for the
majority of RCC cases and is associated
with poor prognosis and limited
treatment options. Despite advances
in surgical resection, immunotherapy,
and targeted therapies, patient
outcomes remain suboptimal, underscoring
the urgent need for novel diagnostic
biomarkers and therapeutic
targets.6-8
Current treatment options
for RCC include partial or radical
nephrectomy for localized disease,
and systemic therapies for advanced
stages. Targeted therapies such as
tyrosine kinase inhibitors (TKIs)
like sunitinib, pazopanib, and
cabozantinib, as well as immune
checkpoint inhibitors (ICIs) like
nivolumab and pembrolizumab, have
improved survival rates in recent
years.9-11 However, these therapies
are not universally effective, and
many patients develop resistance or
experience significant side effects.12,
13 Furthermore, the heterogeneity
of RCC complicates treatment
decisions, and reliable biomarkers to
predict treatment response or disease
progression are lacking.14,15
Given these limitations, there is
a pressing need to identify novel
biomarkers that can aid in early
diagnosis, risk stratification, and
personalized treatment approaches.
Biomarkers capable of distinguishing
aggressive from indolent tumors,
predicting therapeutic response,
and identifying new therapeutic
targets could significantly improve
RCC management.16,17
In recent years, PIWI-interacting
RNAs (piRNAs) and their associated
PIWI-like proteins have emerged
as promising molecules in cancer
research. The PIWI-piRNA
pathway, originally identified in
germline cells, plays a crucial role
in maintaining genomic stability
by silencing transposable elements
and regulating gene expression.9,10
These small non-coding RNAs (~24-
31 nucleotides) interact with PIWI
proteins to modulate various cellular
processes, including proliferation,
differentiation, and apoptosis.11,12
Importantly, piRNAs and PIWIlike
proteins are now recognized
for their roles in somatic tissues,
where their dysregulation has been
implicated in oncogenesis.13,14
In RCC, emerging evidence
suggests that piRNAs and PIWI-like
proteins influence key oncogenic
pathways such as the PI3K/
AKT signaling cascade and the
epithelial-mesenchymal transition
(EMT), both of which are critical
for tumor growth, invasion, and
metastasis.15-17 Specific piRNAs,
such as piR-1742 and piR-31115,
have been associated with aggressive
tumor phenotypes and poor survival
outcomes, while others, like piR-
57125, exhibit potential as metastasis
suppressors.18,19 Furthermore, the
detection of piRNAs in bodily fluids
highlights their potential as noninvasive
biomarkers for early RCC
diagnosis and monitoring.20
Despite these promising
findings, the exact mechanisms
by which piRNAs and PIWIlike
proteins contribute to RCC
pathogenesis remain incompletely
understood. Current research is
limited by small sample sizes,
methodological variability, and
a lack of standardized protocols.
Therefore, a comprehensive
evaluation of existing studies is
essential to elucidate the clinical
relevance of these molecules and
their potential for therapeutic
intervention.
This systematic review aims
to provide a detailed analysis of
the role of piRNAs and PIWIlike
proteins in RCC, focusing
on their implications for disease
pathogenesis, prognosis, and
treatment. By synthesizing current
knowledge, we seek to highlight
the opportunities and challenges
of integrating these molecules into
clinical practice, paving the way for
more personalized approaches to
RCC management.
METHODS
A systematic search was
conducted in PubMed and
ScienceDirect databases in October
2024 using the following keywords:
"piRNAs" OR "PIWI-interacting
RNAs" AND "Renal Cell Carcinoma"
OR "RCC" AND "Pathogenesis"
OR "Therapy" OR "Therapeutic
Targets." The search was limited to studies published between 2014
and 2024 to ensure the inclusion of
recent research. Google Scholar was
used to identify additional relevant
articles and grey literature.
Eligibility Criteria
● Types of Studies:
Randomized controlled trials
(RCTs), cohort studies, and casecontrol
studies.
● Participants: Patients
diagnosed with RCC.
● Interventions: Studies
investigating the role of piRNAs
and PIWI-like proteins in RCC
pathogenesis or therapy.
● Outcomes: Disease
mechanisms, biomarkers,
therapeutic targets, survival rates.
Inclusion Criteria:
● Original research articles
and clinical trials.
● Studies involving human
patients or animal models.
● Articles published in English
within the last 10 years.
Exclusion Criteria:
● Case reports, editorials, and
letters to the editor.
● Studies not focused on RCC
or piRNAs.
● Studies lacking clear
outcome measures related to disease
mechanisms or therapeutic targets.
Selection Process:
The selection process involved
three phases: identification,
screening, and inclusion. Titles
and abstracts were screened
using Rayyan software18, and
discrepancies were resolved through
consensus. After screening 16
studies, 3 were excluded, leaving
13 studies that met the inclusion
criteria (Figure 1).
Quality Assessment
The quality of the included studies
was assessed using the Newcastle-
Ottawa Scale for non-randomized
studies. This tool evaluates the risk
of bias, study validity, and overall
reliability of findings.
RESULTS
The analysis of the 13 selected
studies reveals the significant role
of piRNAs and PIWI-like proteins in
the pathogenesis, progression, and
prognosis of RCC (Table 1). These
molecules influence key oncogenic
pathways and show promise
as diagnostic biomarkers and
therapeutic targets. The following is
a comprehensive synthesis of their
mechanisms and potential clinical
applications.
piR NAs in RCC Pathogenesis
and Metastasis
Several studies have identified
specific piRNAs that promote RCC
progression. Zhang et al. (2023)
found that piR-1742 promotes
RCC malignancy by stabilizing
USP8 through its interaction with
hnRNPU, thereby inhibiting MUC12
ubiquitination and enhancing tumor
growth (Figure 2A).19 Similarly, Du
et al. (2021) reported that piR-31115
activates the PI3K/AKT pathway,
facilitating epithelial-mesenchymal
transition (EMT), which increases
tumor proliferation and invasiveness
(Figure 2B).20 These findings
underscore the oncogenic role of
piRNAs in RCC and highlight their
potential as therapeutic targets.
In contrast, other piRNAs exhibit
tumor-suppressive functions. Ding
et al. (2021) identified piR-57125,
which inhibits RCC metastasis
by downregulating CCL3 and
suppressing the AKT/ERK pathway
(Figure 3).21 This mechanism
reduces the metastatic potential of
RCC cells, suggesting that piR-57125
could serve as a prognostic marker
and therapeutic target to mitigate
disease progression. Li et al. (2015)
conducted deep sequencing of ccRCC tissues and identified piR-
32051, piR-39894, and piR-43607,
which were associated with tumor
metastasis and poor cancer-specific
survival, further demonstrating
the diverse roles of piRNAs in RCC
(Figure 2C).22
Prognostic Value of piRNAs
and PIWI-Like Proteins
The prognostic potential of
piRNAs and PIWI-like proteins
in RCC is supported by multiple
studies. Heng et al. (2022)
identified five piRNA pathway genes
(TDRD7, GPAT2, PLD6, SUV39H1,
and DOM3Z) whose expression
correlated with survival outcomes
in ccRCC patients.23 Among
these, TDRD7 was significantly
overexpressed in tumor tissues and
associated with poor prognosis.
These findings highlight the
potential of piRNA pathway genes
for developing prognostic models.
Zhao et al. (2019) demonstrated
that mitochondrial piRNAs
piR-34536 and piR-51810 were
downregulated in ccRCC tissues,
with lower expression levels
correlating with poor progressionfree
and overall survival. These
mitochondrial piRNAs may serve
as novel prognostic biomarkers
for ccRCC.24 Additionally, Stöhr
et al. (2019) found that elevated
expression of Piwi-like 1 protein
was associated with advanced
tumor stages, distant metastasis,
and reduced survival, suggesting its
utility in identifying high-risk RCC
patients.25
Diagnostic Potential of
piRNAs
The potential of piRNAs as noninvasive
diagnostic biomarkers
is exemplified by the study of
Iliev et al. (2016), who reported
deregulation of piR-823 in RCC
patients. While piR-823 was
downregulated in tumor tissues,
its levels were elevated in serum
and urine, indicating its utility for
non-invasive diagnosis and disease
monitoring.26 Similarly, Busch et al.
(2015) identified piR-30924, piR-
57125, and piR-38756 as prognostic
markers, with their differential
expression distinguishing between
metastatic and non-metastatic RCC
cases.27
Mechanistic Insights and
Molecular Pathways
Several studies explored the
molecular mechanisms by which
piRNAs and PIWI-like proteins
influence RCC. Sun et al. (2022)
demonstrated that dysregulated
expression of tumor suppressor
genes HIC1 and RassF1A alters
cytoskeletal structure and piRNA
content in extracellular vesicles,
providing insights into the molecular
changes driving RCC progression.28
Al-Janabi et al. (2014) investigated
the expression of Piwil 1-4 genes and
found significant correlations with
clinicopathological parameters,
suggesting age-related molecular
pathways in RCC development.29
Furthermore, Ding et al. (2021)
highlighted the broader role of
small non-coding RNAs, including
piRNAs, in RCC pathogenesis,
emphasizing the need for more
extensive research to elucidate
their mechanisms.30 This study,
along with others, underscores the
complex interplay between piRNAs,
PIWI-like proteins, and oncogenic
pathways such as PI3K/AKT and
AKT/ERK.
Limitations
Despite the promising findings,
several challenges remain. Most
studies included small sample
sizes, limiting the statistical power
and generalizability of the results.
Methodological inconsistencies,
such as differences in detection
techniques and data analysis, hinder
the ability to compare findings
across studies. Additionally, many
conclusions are based on in vitro
experiments or univariate analyses,
raising concerns about potential
confounding factors like tumor stage
and other prognostic features.
DISCUSSION
The findings of this systematic
review underscore the growing
body of evidence highlighting the
critical roles of piRNAs and PIWIlike
proteins in the development,
progression, and prognosis of RCC.
These molecules are implicated in
key oncogenic processes, including
gene regulation, tumor proliferation,
invasion, and metastasis. The studies
analyzed provide a multifaceted
view of how piRNAs and PIWI-like
proteins contribute to RCC biology,
offering new insights into potential
diagnostic and therapeutic avenues
(Table 2).
Several piRNAs, such as piR-
1742 and piR-31115, have been
shown to promote RCC progression
by interacting with pathways that
regulate cell proliferation and
invasion.22, 27, 28, 29, 31 Specifically,
piR-1742 enhances tumor
growth by stabilizing USP8 and
inhibiting MUC12 ubiquitination,
as demonstrated by Zhang et al.
(2023).29 Similarly, piR-31115
activates the PI3K/AKT pathway
and facilitates EMT, promoting cell
proliferation and metastasis.20
These findings suggest that
inhibiting these piRNAs or their
associated pathways could provide
therapeutic benefits, particularly in
aggressive RCC phenotypes.
Mitochondrial piRNAs, such as
piR-34536 and piR-51810, identified
by Zhao et al. (2019), represent a
novel class of biomarkers associated
with RCC prognosis.24 Their
downregulation correlates with poor
survival outcomes, indicating their
potential utility in early detection
and prognosis. Furthermore, piR-
57125 has been shown to suppress
metastasis by downregulating
CCL3 and inhibiting the AKT/
ERK pathway.21 These findings
highlight the functional significance
of piRNAs in metastatic control and
suggest that therapeutic strategies
aimed at restoring or enhancing the
expression of tumor-suppressive
piRNAs may inhibit disease
progression.
The role of PIWI-like proteins,
particularly Piwi-like 1, adds
another dimension to RCC research.
Stöhr et al. (2019) demonstrated
that elevated expression of Piwilike
1 correlates with advanced
tumor grades and worse survival,
marking it as a potential prognostic
biomarker, especially for high-risk
patients.25 The co-expression of Piwil
1-4 genes with clinicopathological
parameters, as noted by Al-Janabi
et al. (2014), supports the potential
diagnostic and prognostic relevance
of these proteins.29 Targeting PIWIlike
proteins could thus complement
existing RCC therapies, particularly
in personalized medicine
approaches.
The therapeutic potential of
targeting piRNAs and PIWI-like
proteins is vast, though still in its
early stages. Inhibitors of oncogenic
piRNAs, such as piR-1742 or piR-
31115, could be developed to disrupt
key pathways like PI3K/AKT and
EMT, which are critical for tumor
growth and metastasis.19,20
Conversely, restoring the expression
of tumor-suppressive piRNAs,
such as piR-57125, could help
mitigate metastatic spread.30 These
approaches could be integrated with
current therapies, such as TKIs, ICIs,
and targeted molecular therapies,
to enhance efficacy and overcome
resistance.
Combination therapies that
incorporate piRNA or PIWI-like
protein modulation with existing
RCC treatments could provide
synergistic effects. For example,
combining piRNA-targeted therapies
with immunotherapy may enhance
the immune response against RCC
by modulating immune-related
pathways.22, 25, 28-30 Additionally,
integrating piRNA-based strategies
with radiotherapy or chemotherapy
could sensitize tumors to treatment,
potentially improving outcomes for
patients with advanced or refractory
RCC.27, 30
Despite these promising
findings, several challenges
remain. The current understanding
of piRNA biology is limited,
particularly regarding their
regulatory mechanisms in somatic
cells and cancer. The heterogeneity
of RCC, coupled with variations
in study design, sample sizes,
and methodologies, complicates
the synthesis of consistent
conclusions. For instance,
discrepancies in the expression
patterns of piR-823 across different
biological samples (tumor tissue,
serum, and urine) highlight the
complexity of piRNA regulation
and the need for standardized
protocols.10, 11, 12
Moreover, many studies rely
on in vitro data or analyses limited
to univariate associations, making
it difficult to establish causative
relationships. Larger, wellstructured
cohorts and multivariate
analyses are essential to validate
these findings and confirm the
clinical relevance of piRNAs and
PIWI-like proteins. Standardizing
detection methods, such as qRT-PCR
and next-generation sequencing,
and ensuring reproducibility across
laboratories will be critical for
advancing piRNA research in RCC.
FUTURE DIRECTIONS
Future research should
focus on elucidating the precise
mechanisms through which
piRNAs and PIWI-like proteins
influence RCC pathogenesis.
Investigating their roles in drug
resistance, immune evasion, and
the tumor microenvironment could
uncover new therapeutic targets.
Additionally, clinical trials assessing
the safety and efficacy of piRNAtargeted
therapies in combination
with existing treatments are needed
to translate these findings into clinical
practice. As the field advances,
piRNAs and PIWI-like proteins
may emerge as key components of
personalized medicine strategies,
ultimately improving the diagnosis,
prognosis, and treatment of RCC.
CONCLUSIONS
This systematic review
highlights the potential role of
piRNAs and PIWI-like proteins as biomarkers and therapeutic targets
in RCC. Our analysis reveals that
molecules like piR-1742, piR-31115,
and Piwi-like 1 are associated with
key oncogenic processes, including
tumor proliferation, invasion, and
poor survival outcomes. These
findings suggest that piRNAs may
serve as diagnostic tools, particularly
for identifying aggressive RCC
phenotypes.
However, the current evidence
is limited by the predominance of in
vitro studies and univariate analyses.
The associations identified may
be influenced by other prognostic
factors, such as tumor stage, grade,
or other systemic conditions. To
strengthen these conclusions, future
research should focus on validating
these molecules in large, wellstructured
cohorts and conducting
multivariate analyses to determine
their independent prognostic value.
Availability of data and
Materials
All data generated or analyzed
during this study are included
in this published article [and its
supplementary information files].
Ethical Approval
This article does not contain any
studies with human participants or
animals performed by any of the
authors.
Conflicts of interest
All authors declare no conflicts
of interest, financial or otherwise,
related to this manuscript.
Funding Sources
This study was not supported by
any sponsor or funder.
Contributions
All authors played a substantial
role in conception, design,
acquisition, analysis, interpretation,
writing, and critical review of the
manuscript. All authors approved
the final content and accepted
responsibility for its accuracy and
integrity.
Abbreviations
ccRCC: Clear Cell Renal Cell
Carcinoma, USP: Ubiquitin-Specific
Protease, hnRNPU: Heterogeneous
Nuclear Ribonucleoprotein U, MUC:
Mucin, PI3K/AKT: Phosphoinositide
3-Kinase/Protein Kinase B, EMT:
Epithelial-Mesenchymal Transition,
AKT/ERK: AKT/Extracellular
Signal-Regulated Kinase, TCGA:
The Cancer Genome Atlas, GSEA:
Gene Set Enrichment Analysis, TICs:
Tumor Immune Infiltrating Cells,
AUC: Area Under the Curve, TMA:
Tissue Microarray, ROC: Receiver
Operating Characteristic, qRT-PCR:
Quantitative Real-Time Polymerase
Chain Reaction, FFPE: Formalin-
Fixed Paraffin-Embedded.
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* # # Correspondence:Jheremy Sebastian Reyes Barreto
Cancer and Molecular Medicine Research Group (CAMMO), Bogotá D.C., Colombia Carrera
Email: js.reyesb@uniandes.edu.co