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Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 23821

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Prof. Dr. Kerstin Junker

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Department of Urology and Pediatric Urology, Saarland University, Kirrberger Straße 100, Gebäude 6, 66424 Homburg/Saar, Germany
Interests: tumor biomarkers; tumor microenvironment; miRNA; extracellular vesicles; urological malignancies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-coding RNAs (ncRNAs) are important regulators of cellular signaling in physiological and pathophysiological processes, including tumor development and progression. ncRNAs are divided into two major classes: long ncRNAs (lncRNAs, >200 nucleotides) and small ncRNAs (<200 nucleotides) including microRNAs (miRNAs), small interfering RNAs (siRNAs), and PIWI-interacting RNAs (piRNAs). Their biological role can be diverse depending on their tissue and cellular context. ncRNAs generate complex regulatory networks and can compete against each other for binding to mRNAs, behaving as so-called competing endogenous RNA (ceRNA). The understanding of their diverse function as key regulators of gene expression facilitates the development of new molecular therapeutic strategies on the one hand and biomarkers in tumor tissues and body fluids on the other.

During the last several years, ncRNAs have been intensively investigated in all urological malignancies in order to understand important signaling pathways and to identify biomarkers which have yet to be discovered.

This Special Issue will highlight ncRNAs in diverse urological cancer types such as prostate, kidney, urothelial, testicular, and penile cancer. Original research articles as well reviews will show the potential of ncRNAs as key players in tumorigenesis, as therapeutic targets, as well as biomarkers for diagnosis, prognostic evaluation, and therapy prediction.

Prof. Dr. Kerstin Junker
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

non-coding RNAs (ncRNAs)
miRNAs
lncRNAs
piRNAs
siRNAs
snRNAs
snoRNAs
exosomes
extracellular vesicles
biomarker
liquid biopsy

Published Papers (9 papers)

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Research

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18 pages, 3741 KiB

Open AccessArticle

Long Noncoding RNA LINC02470 Sponges MicroRNA-143-3p and Enhances SMAD3-Mediated Epithelial-to-Mesenchymal Transition to Promote the Aggressive Properties of Bladder Cancer

by Cheng-Shuo Huang, Chen-Hua Tsai, Cheng-Ping Yu, Ying-Si Wu, Ming-Fong Yee, Jar-Yi Ho and Dah-Shyong Yu

Cancers 2022, 14(4), 968; https://doi.org/10.3390/cancers14040968 - 15 Feb 2022

Cited by 13 | Viewed by 2372

Abstract

Bladder cancer progression and metastasis have become major threats in clinical practice, increasing mortality and therapeutic refractoriness; recently, epigenetic dysregulation of epithelial-to-mesenchymal transition (EMT)-related signaling pathways has been explored. However, research in the fields of long noncoding RNA (lncRNA) and competing endogenous RNA (ceRNA) regulation in bladder cancer progression is just beginning. This study was designed to determine potential EMT-related ceRNA regulation in bladder cancer progression and elucidate the underlying mechanisms that provoke aggressiveness. After screening the intersection of bioinformatic pipelines, LINC02470 was identified as the most upregulated lncRNA during bladder cancer initiation and progression. Both in vitro and in vivo biological effects indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and tumorigenicity. On a molecular level, miR-143-3p directly targets and reduces both LINC02470 and SMAD3 RNA expression. Therefore, the LINC02470–miR-143-3p–SMAD3 ceRNA axis rescues SMAD3 translation upon LINC02470 sponging miR-143-3p, and SMAD3 consequently activates the TGF-β-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-β-induced EMT through the miR-143-3p/SMAD3 axis, thereby aggravating bladder cancer progression. Our study warrants further investigation of LINC02470 as an indicatively prognostic marker of bladder cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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19 pages, 3083 KiB

Open AccessArticle

Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis

by Tatiane Katsue Furuya, Claudio Bovolenta Murta, Alexis Germán Murillo Carrasco, Miyuki Uno, Laura Sichero, Luisa Lina Villa, Leonardo Cardilli, Rafael Ferreira Coelho, Giuliano Betoni Guglielmetti, Mauricio Dener Cordeiro, Katia Ramos Moreira Leite, William Carlos Nahas, Roger Chammas and José Pontes, Jr.

Cancers 2021, 13(19), 4745; https://doi.org/10.3390/cancers13194745 - 23 Sep 2021

Cited by 7 | Viewed by 2544

Abstract

Penile cancer (PeC) carcinogenesis is not fully understood, and no biomarkers are reported in clinical practice. We aimed to investigate molecular signatures based on miRNA and mRNA and perform an integrative analysis to identify molecular drivers and pathways for PeC development. Affymetrix miRNA microarray was used to identify differentially expressed miRNAs (DEmiRs) comparing 11 tumoral tissues (TT) paired with non-neoplastic tissues (NNT) with further validation in an independent cohort (n = 13). We also investigated the mRNA expression of 83 genes in the total sample. Experimentally validated targets of DEmiRs, miRNA-mRNA networks, and enriched pathways were evaluated in silico. Eight out of 69 DEmiRs identified by microarray analysis were validated by qRT-PCR (miR-145-5p, miR-432-5p, miR-487b-3p, miR-30a-5p, miR-200a-5p, miR-224-5p, miR-31-3p and miR-31-5p). Furthermore, 37 differentially expressed genes (DEGs) were identified when comparing TT and NNT. We identified four downregulated DEmiRs (miR-30a-5p, miR-432-5p, miR-487b-3p, and miR-145-5p) and six upregulated DEGs (IL1A, MCM2, MMP1, MMP12, SFN and VEGFA) as potential biomarkers in PeC by their capacity of discriminating TT and NNT with accuracy. The integration analysis showed eight dysregulated miRNA-mRNA pairs in penile carcinogenesis. Taken together, our findings contribute to a better understanding of the regulatory roles of miRNAs and altered transcripts levels in penile carcinogenesis. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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15 pages, 2383 KiB

Open AccessArticle

MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma

by Lisa Kinget, Eduard Roussel, Annelies Verbiest, Maarten Albersen, Cristina Rodríguez-Antona, Osvaldo Graña-Castro, Lucía Inglada-Pérez, Jessica Zucman-Rossi, Gabrielle Couchy, Sylvie Job, Aurélien de Reyniès, Annouschka Laenen, Marcella Baldewijns and Benoit Beuselinck

Cancers 2021, 13(12), 3099; https://doi.org/10.3390/cancers13123099 - 21 Jun 2021

Cited by 16 | Viewed by 2900

Abstract

Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel–Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2α are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2α, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2α, VEGFR1 and/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2α expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2α inhibitor belzutifan. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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13 pages, 1312 KiB

Open AccessArticle

Prediction of Grade Reclassification of Prostate Cancer Patients on Active Surveillance through the Combination of a Three-miRNA Signature and Selected Clinical Variables

by Paolo Gandellini, Chiara Maura Ciniselli, Tiziana Rancati, Cristina Marenghi, Valentina Doldi, Rihan El Bezawy, Mara Lecchi, Melanie Claps, Mario Catanzaro, Barbara Avuzzi, Elisa Campi, Maurizio Colecchia, Fabio Badenchini, Paolo Verderio, Riccardo Valdagni and Nadia Zaffaroni

Cancers 2021, 13(10), 2433; https://doi.org/10.3390/cancers13102433 - 18 May 2021

Cited by 7 | Viewed by 1531

Abstract

Active surveillance (AS) has evolved as a strategy alternative to radical treatments for very low risk and low-risk prostate cancer (PCa). However, current criteria for selecting AS patients are still suboptimal. Here, we performed an unprecedented analysis of the circulating miRNome to investigate whether specific miRNAs associated with disease reclassification can provide risk refinement to standard clinicopathological features for improving patient selection. The global miRNA expression profiles were assessed in plasma samples prospectively collected at baseline from 386 patients on AS included in three independent mono-institutional cohorts (training, testing and validation sets). A three-miRNA signature (miR-511-5p, miR-598-3p and miR-199a-5p) was found to predict reclassification in all patient cohorts (training set: AUC 0.74, 95% CI 0.60–0.87, testing set: AUC 0.65, 95% CI 0.51–0.80, validation set: AUC 0.68, 95% CI 0.56–0.80). Importantly, the addition of the three-miRNA signature improved the performance of the clinical model including clinicopathological variables only (AUC 0.70, 95% CI 0.61–0.78 vs. 0.76, 95% CI 0.68–0.84). Overall, we trained, tested and validated a three-miRNA signature which, combined with selected clinicopathological variables, may represent a promising biomarker to improve on currently available clinicopathological risk stratification tools for a better selection of truly indolent PCa patients suitable for AS. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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15 pages, 1698 KiB

Open AccessArticle

Small RNAs in Seminal Plasma as Novel Biomarkers for Germ Cell Tumors

by Nina Mørup, Rytis Stakaitis, Ieva Golubickaite, Meritxell Riera, Marlene Danner Dalgaard, Mikkel H. Schierup, Niels Jørgensen, Gedske Daugaard, Anders Juul and Kristian Almstrup

Cancers 2021, 13(10), 2346; https://doi.org/10.3390/cancers13102346 - 13 May 2021

Cited by 6 | Viewed by 2678

Abstract

Circulating miRNAs secreted by testicular germ cell tumors (TGCT) show great potential as novel non-invasive biomarkers for diagnosis of TGCT. Seminal plasma (SP) represents a biofluid closer to the primary site. Here, we investigate whether small RNAs in SP can be used to diagnose men with TGCTs or the precursor lesions, germ cell neoplasia in situ (GCNIS). Small RNAs isolated from SP from men with TGCTs (n = 18), GCNIS-only (n = 5), and controls (n = 25) were sequenced. SP from men with TGCT/GCNIS (n = 37) and controls (n = 22) were used for validation by RT-qPCR. In general, piRNAs were found at lower levels in SP from men with TGCTs. Ten small RNAs were found at significantly (q-value < 0.05) different levels in SP from men with TGCT/GCNIS than controls. Random forests classification identified sets of small RNAs that could detect either TGCT/GCNIS or GCNIS-only with an area under the curve of 0.98 and 1 in ROC analyses, respectively. RT-qPCR validated hsa-miR-6782-5p to be present at 2.3-fold lower levels (p = 0.02) in the SP from men with TGCTs compared with controls. Small RNAs in SP show potential as novel biomarkers for diagnosing men with TGCT/GCNIS but validation in larger cohorts is needed. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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22 pages, 1053 KiB

Open AccessArticle

MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma

by Lisa Kinget, Eduard Roussel, Diether Lambrechts, Bram Boeckx, Loïc Vanginderhuysen, Maarten Albersen, Cristina Rodríguez-Antona, Osvaldo Graña-Castro, Lucía Inglada-Pérez, Annelies Verbiest, Jessica Zucman-Rossi, Gabrielle Couchy, Stefano Caruso, Annouschka Laenen, Marcella Baldewijns and Benoit Beuselinck

Cancers 2021, 13(7), 1554; https://doi.org/10.3390/cancers13071554 - 28 Mar 2021

Cited by 10 | Viewed by 2493

Abstract

Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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15 pages, 5502 KiB

Open AccessArticle

miRNA Expression Characterizes Histological Subtypes and Metastasis in Penile Squamous Cell Carcinoma

by Hiresh Ayoubian, Joana Heinzelmann, Sebastian Hölters, Oybek Khalmurzaev, Alexey Pryalukhin, Philine Loertzer, Julia Heinzelbecker, Stefan Lohse, Carol Geppert, Hagen Loertzer, Heiko Wunderlich, Rainer M. Bohle, Michael Stöckle, Vsevolod Borisovich Matveev, Arndt Hartmann and Kerstin Junker

Cancers 2021, 13(6), 1480; https://doi.org/10.3390/cancers13061480 - 23 Mar 2021

Cited by 10 | Viewed by 2987

Abstract

Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs (p ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, p ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, p ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs (p ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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Review

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16 pages, 751 KiB

Open AccessReview

Unveiling the World of Circulating and Exosomal microRNAs in Renal Cell Carcinoma

by José Pedro Sequeira, Vera Constâncio, João Lobo, Rui Henrique and Carmen Jerónimo

Cancers 2021, 13(21), 5252; https://doi.org/10.3390/cancers13215252 - 20 Oct 2021

Cited by 8 | Viewed by 1965

Abstract

Renal cell carcinoma is the third most common urological cancer. Despite recent advances, late diagnosis and poor prognosis of advanced-stage disease remain a major problem, entailing the need for novel early diagnosis tools. Liquid biopsies represent a promising minimally invasive clinical tool, providing real-time feedback of tumor behavior and biological potential, addressing its clonal evolution and representing its heterogeneity. In particular, the study of circulating microRNAs and exosomal microRNAs in liquid biopsies experienced an exponential increase in recent years, considering the potential clinical utility and available technology that facilitates implementation. Herein, we provide a systematic review on the applicability of these biomarkers in the context of renal cell carcinoma. Issues such as additional benefit from extracting microRNAs transported in extracellular vesicles, use for subtyping and representation of different histological types, correlation with tumor burden, and prediction of patient outcome are also addressed. Despite the need for more conclusive research, available data indicate that exosomal microRNAs represent a robust minimally invasive biomarker for renal cell carcinoma. Thus, innovative research on microRNAs and novel detection techniques are likely to provide clinically relevant biomarkers, overcome current clinical challenges, and improve patient management. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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22 pages, 358 KiB

Open AccessReview

Role of Metastasis-Related microRNAs in Prostate Cancer Progression and Treatment

by Su Jung Oh-Hohenhorst and Tobias Lange

Cancers 2021, 13(17), 4492; https://doi.org/10.3390/cancers13174492 - 06 Sep 2021

Cited by 29 | Viewed by 3318

Abstract

Prostate cancer (PCa) is one of the most prevalent cancer types in males and the consequences of its distant metastatic deposits are the leading cause of PCa mortality. Therefore, identifying the causes and molecular mechanisms of hematogenous metastasis formation is of considerable clinical importance for the future development of improved therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs. Numerous studies have identified miRNAs as promotors or inhibitors of metastasis and revealed, in part, their targeting pathways in PCa. Because miRNAs are remarkably stable and can be detected in both tissue and body fluid, its potential as specific biomarkers for metastasis and therapeutic response is also currently under preclinical evaluation. In the present review, we focus on miRNAs that are supposed to initiate or suppress metastasis by targeting several key mRNAs in PCa. Metastasis-suppressing miRNAs include miR-33a-5p, miR-34, miR-132 and miR-212, miR-145, the miR-200 family (incl. miR-141-3p), miR-204-5p, miR-532-3p, miR-335, miR-543, miR-505-3p, miR 19a 3p, miR-802, miR-940, and miR-3622a. Metastasis-promoting RNAs, such as miR-9, miR-181a, miR-210-3, miR-454, miR-671-5p, have been shown to increase the metastatic potential of PCa cells. Other metastasis-related miRNAs with conflicting reports in the literature are also discussed (miR-21 and miR-186). Finally, we summarize the recent developments of miRNA-based therapeutic approaches, as well as current limitations in PCa. Taken together, the metastasis-controlling miRNAs provide the potential to be integrated in the strategy of diagnosis, prognosis, and treatment of metastatic PCa. Nevertheless, there is still a lack of consistency between certain miRNA signatures and reproducibility, which impedes clinical implementation. Full article

(This article belongs to the Special Issue Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development)

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Non-Coding RNAs in Urological Malignancies: Relevance for Tumorigenesis and Biomarker Development

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