LncRNA PVT1 (plasmacytoma variant translocation 1) has become a staple of the lncRNA profile in patients with renal cell carcinoma (RCC). Common dysregulation in renal tumors outlines the essential role of PVT1 in the development of RCC. There is already a plethora of publications trying to uncover the cellular mechanisms of PVT1-mediated regulation and its potential exploitation in management of RCC. In this review, we summarize the literature focused on PVT1 in RCC and aim to synthesize the current knowledge on its role in the cells of the kidney. Further, we provide an overview of the lncRNA profiling studies that have identified a more or less significant association of PVT1 with the clinical behavior of RCC. Based on our search, we analyzed the 17 scientific papers discussed in this review that provide robust support for the indispensable role of PVT1 in RCC development and future personalized therapy.

Background Renal cell carcinoma is difficult to diagnose and unpredictable in disease course and severity. There are no specific biomarkers for diagnosis and prognosis estimation feasible in clinical practice. Long non‐coding RNAs (lncRNAs) have emerged as potent regulators of gene expression in recent years. Aside from their cellular role, their expression patterns could be used as a biomarker of ongoing pathology. Methods In this work, we used next‐generation sequencing for global lncRNA expression profiling in tumor and non‐tumor tissue of RCC patients. The four candidate lncRNAs have been further validated on an independent cohort. PVT1, as the most promising lncRNA, has also been studied using functional in vitro tests. Results Next‐generation sequencing showed significant dysregulation of 1163 lncRNAs; among them top 20 dysregulated lncRNAs were AC061975.7, AC124017.1, AP000696.1, AC148477.4, LINC02437, GATA3‐AS, LINC01762, LINC01230, LINC01271, LINC01187, LINC00472, AC007849.1, LINC00982, LINC01543, AL031710.1, and AC019197.1 as down‐regulated lncRNAs; and SLC16A1‐AS1, PVT1, LINC0887, and LUCAT1 as up‐regulated lncRNAs. We observed statistically significant dysregulation of PVT1, LUCAT1, and LINC00982. Moreover, we studied the effect of artificial PVT1 decrease in renal cell line 786–0 and observed an effect on cell viability and migration. Conclusion Our results show not only the diagnostic but also the therapeutic potential of PVT1 in renal cell carcinoma.

Introduction: Renal cell carcinoma (RCC) is due to its asymptomatic nature usually diagnosed too late or incidentally during the examination for other indications. There is currently none sufficiently sensitive and reliable biomarker for diagnosis, prediction of the disease development or therapeutic outcome in RCC. Long non-coding RNAs (lncRNAs), RNA molecules regulating gene expression present a group of potential biomarkers as their specific expression profiles have been described in many types of tumors including RCC. Main aim of this study was to analyse global expression profiles of lncRNAs by RNA sequencing, compare them with clinical behaviour of the cancer and to characterize functions of the candidate lncRNAs in vitro. Material and methods: Using next-generation sequencing of RNA from the fresh frozen tissue of 22 patients with RCC we compared expression of lncRNAs in tumor and adjacent non-tumor renal parenchyma. Expression of candidate lncRNAs biomarkers (PVT1, LUCAT1, LINC00982 and SLC16A-AS1) has been validated using qPCR on an independent cohort of 30 patients, results have been statistically evaluated using Mann-Whitney U-test, ROC analysis and were correlated with the clinical stage and Fuhrman grade. Expression of PVT1 was silenced using siRNAs in RCC cell cultures (786-0) and functional characteristics of PVT1 have been studied using MTT test, cell counting and scratch-wound assay. Results: Using the DESeq tool, 1163 deregulated lncRNAs have been identified in patients with RCC when lncRNA profiles of tumors and paired renal parenchyma were compared (538 with increased and 625 with decreased expression levels in tumors). PVT1 (AUC 0,8567, sensitivity 86,67%, specificity 76,67%) and LUCAT1 (AUC 0,7756, sensitivity and specificity 90%) have significantly increased expression and LINC00982 (AUC 0,9578, sensitivity 76,67% and specificity 66,67%) has significantly decreased expression (p < 0,001) also in the validation phase. Statistically significant difference in expression of SLC16A-AS1 has not been observed. Partial effect on migration and proliferation has been observed in PVT1 after the transfection by short interfering RNA. Conclusion: PVT1, LUCAT1 and LINC00982 are a potential diagnostic biomarkers of RCC. Their prognostic potential has not been identified. PVT1 indicated oncogenic functioning in RCC cell lines. This work was supported by Ministry of Health of the Czech Republic, grant nr. NV18-03-00554 and by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601). All rights reserved. Citation Format: Adela Kubickova, Julia Bohosova, Karolina Trachtova, Jiri Sana, Alexandr Poprach, Michal Stanik, Jan Dolezel, Michal Fedorko, Dalibor Pacik, Marek Svoboda, Ondrej Slaby. Long non-coding RNA PVT1 is a promising diagnostic biomarker with oncogenic functioning in renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3124.

Východiska: Jedním z moderních přístupů identifikace bio markerů nádorových onemocnění, a to jak na tkáňové úrovni, tak i v tělních tekutinách, je profilování exprese mikroRNA (miRNA). miRNA tvoří skupinu téměř 3 000 krátkých, 18-25 nukleotidů dlouhých nekódujících RNA. Slouží jako regulační prvky, které řídí expresi genů na posttranskripční úrovni, tj. na úrovni molekul mRNA. Schopnost miRNA inhibovat translaci či indukovat degradaci onkogenů a nádorových supresorů je podstatou jejich zapojení do procesů kancerogeneze. Důkazů o funkcích miRNA v regulaci procesů, jako jsou apoptóza, buněčná proliferace, diferenciace či invazivita, neustále přibývá. Analýza expresních profilů miRNA je proto stále častěji využívána pro účely molekulární dia gnostiky nádorových onemocnění, analogicky jako je tomu u studií založených na profilování kódujících RNA. Z hlediska analytického využití je podstatná skutečnost, že miRNA jsou vysoce stabilní v tělních tekutinách vč. slin a vyskytují se zde v relativně vysokých hladinách. miRNA ve slinách již byly pro dia gnostické účely úspěšně testovány u řady nádorových onemocnění, přičemž hlavní výhodou slin jako bio logického materiálu je skutečnost, že jsou získatelné zcela neinvazivně. Cíl: Cílem přehledového článku je shrnout dosavadní míru poznání z oblasti cirkulujících miRNA u nádorových onemocnění se zaměřením na využití miRNA ve slinách pro účely onkologické dia gnostiky. Klíčová slovamikroRNA -sliny -dia gnostika -nádorové onemocnění SummaryBackground: A modern approach to identify bio markers of solid cancers in tissues and body fluids is based on microRNA (miRNA) expression profiling. miRNAs are a group of approximately 3.000 short noncod ing RNAs contain ing 18-25 nucleotides that regulate gene expression at the post-transcriptional (mRNA) level. The abilities of miRNAs to inhibit the translation or induce degradation of oncogenes and tumor suppressors indicate that they are involved in carcinogenesis. There is increas ing evidence that miRNAs regulate apoptosis, cell proliferation, differentiation, and invasion. miRNA expression profiles are therefore often analyzed for molecular dia gnostics of solid cancers, similar to analyses based on mRNA profiling. It is important that miRNAs are highly stable and present at high levels in body fluids, includ ing saliva, for analytic usage. miRNAs in saliva have been successfully tested as potential dia gnostic biomarkers of many solid cancers. The main advantage of these miRNAs is that saliva samples can be collected non-invasively. Aim: This review aims to summarize current knowledge of circulat ing miRNAs in solid cancers, with a focus on the use of miRNAs in saliva for oncology dia gnostics.