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.

Keywords

piRNAs, Renal Cell Carcinoma, PIWI-interacting RNAs, Biomarkers, Therapeutic targets

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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