Východiska: Za poslední desetiletí přibyly stovky studií, jež souhlasně prokázaly, že krátké nekódující RNA jsou slibnými diagnostickými, prognostickými a prediktivními biomarkery nádorových onemocnění. Významnou podskupinu těchto molekul představují RNA interagující s PIWI proteiny, označované jako piRNA. Tyto krátké RNA se podílejí na regulaci genové exprese na transkripční nebo post-transkripční úrovni, jejich hlavní úlohou je však epigenetické umlčování transpozibilních elementů LINE a SINE, čímž významně přispívají k udržení genomové stability. Dále se účastní důležitých buněčných procesů, jakými jsou gametogeneze, segregace chromozomů či sebeobnova kmenových buněk. Přestože byly piRNA poprvé detekovány v zárodečných buňkách, bylo zjištěno, že se vyskytují ve vysokých hladinách také v jiných lidských tkáních, přičemž jejich exprese vykazuje tkáňovou specificitu. První studie rovněž prokázaly změněný expresní profil piRNA u pacientů s nádorovými onemocněními. Funkce těchto molekul v procesu kancerogeneze však zatím zůstávají neobjasněné. Do popředí zájmu se v poslední době též dostávají volné cirkulující piRNA v tělních tekutinách, které nabízejí široké využití pro včasný záchyt nádorových onemocnění, predikci léčebné odpovědi či stanovení prognózy pacientů. Cíl: Tento přehledový článek jako první v českém jazyce shrnuje dosavadní poznatky o biogenezi piRNA, o jejich strategii při umlčování transpozibilních elementů a dalších genů. Poskytuje rovněž ucelený přehled o piRNA s deregulovanou expresí u lidských nádorových onemocnění a klade důraz na jejich potenciální diagnostické a terapeutické využití.

Background: In the past few years, a number of studies have suggested that small non-coding RNAs could be promising diagnostic, prognostic and predictive biomarkers in oncology. Recently, small RNAs interacting with PIWI proteins (piRNAs) have been described. These small RNAs regulate gene expression at transcriptional and post-transcriptional levels; however, they appear to be specifically involved in silencing the transposable elements LINE and SINE and are thus considered to contribute to genomic stability. Furthermore, piRNAs participate also in other important biological processes, such as gametogenesis, chromosome segregation, and stem cell self-renewal. Although their expression was first noted in germ line cells, they are now known to be present in all tissue types and their expression is highly tissue-specific. In addition, piRNA expression is dysregulated in tumor tissues. Nevertheless, the exact function of these molecules in cancerogenesis is not known. Recently, free circulating piRNAs were reported to be stably present in body fluids, suggesting that they could serve as promising noninvasive biomarkers to enable early diagnosis, therapy response prediction, and accurate prognosis prediction of cancer patients. Aim: The aim of this review is to summarize current knowledge about piRNA biogenesis and their functions in the regulation of gene expression and transposons silencing. In addition, the review focuses on piRNAs that show dysregulated expression in different types of cancers and that could serve as potential diagnostic biomarkers and/or therapeutic targets.

• Klíčová slova
• umlčování transpozonů,
• MeSH
• biogeneze organel MeSH
• karcinogeneze MeSH
• lidé MeSH
• malá interferující RNA * MeSH
• nádorové biomarkery genetika   MeSH
• nádory * diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Transposable elements (TEs) are powerful drivers of genome evolutionary dynamics but are principally deleterious to the host organism by compromising the integrity and function of the genome. The transposition of TEs may result in mutations and DNA damage. DNA double-strand breaks (DSBs), which may be caused by the transposition, are one of the processes directly linked to aging. TEs may thus be considered to constitute an internal source of aging and the frequency of transposition may, in turn, be considered to affect the pace of aging. The PIWI-piRNA pathway is a widespread strategy used by most animals to effectively suppress transposition. Interestingly, the PIWI-piRNA pathway is expressed predominantly in the animal germline, a more or less continuous immortal lineage set aside after the first few cell divisions of a developing embryo. Recent findings further imply that the PIWI-piRNA pathway and TE suppression constitute an important mechanism regulating aging. This article discusses the proposed role of the PIWI-piRNA pathway in setting the pace of aging as well as the possible mechanisms underlying this process.

• MeSH
• Argonaut proteiny * genetika   metabolismus   MeSH
• buněčné dělení genetika   MeSH
• lidé MeSH
• malá interferující RNA * genetika   metabolismus   MeSH
• poškození DNA * MeSH
• stárnutí * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

OBJECTIVE: The PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA). METHODS: The expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot. The expression of piRNAs was quantified by next generation small RNA sequencing (NGS). The regulation of PIWI/piRNAs, proliferation and methylation of LINE-1 after silencing of PIWIL genes were studied. RESULTS: PIWIL2 and 4 mRNA were similarly expressed in synovial tissues and SF from RA and OA patients. However, on the protein level only PIWIL4 was strongly expressed in SF. Using NGS up to 300 piRNAs were identified in all SF without significant differences in expression levels between RA and OASF. Of interest, the analysis of the co-expression of the detected piRNAs revealed a less tightly regulated pattern of piRNA-823, -4153 and -16659 expression in RASF. In RASF and OASF, stimulation with TNFα+IL1β/TLR-ligands further significantly increased the expression levels of PIWIL2 and 4 mRNA and piRNA-16659 was significantly (4-fold) induced upon Poly(I:C) stimulation. Silencing of PIWIL2/4 neither affect LINE-1 methylation/expression nor proliferation of RASF. CONCLUSION: We detected a new class of small regulatory RNAs (piRNAs) and their specific binding partners (PIWIL2/4) in synovial fibroblasts. The differential regulation of co-expression of piRNAs in RASF and the induction of piRNA/Piwi-proteins by innate immune stimulators suggest a role in inflammatory processes.

• MeSH
• Argonaut proteiny genetika   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dlouhé rozptýlené jaderné elementy MeSH
• fibroblasty patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• osteoartróza genetika   metabolismus   patologie   MeSH
• proteiny genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• revmatoidní artritida genetika   metabolismus   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• synoviální membrána patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Glioblastom (GBM) je nejčastěji se vyskytující primární nádor mozku astrocytárního původu. Navzdory pokrokům v oblasti molekulární patologie a onkologie stále neexistují klinicky využitelné přístupy umožňující jednak klasifikovat pacienty dle jejich prognózy, ani překonat rezistenci GBM vůči konvenční terapii. To vede k časným relapsům a krátkému přežívání pacientů s GBM. Biologické chování GBM je dáváno do souvislosti s přítomností glioblastomových kmenových buněk (GSC), subpopulace vyznačující se vlastnostmi pluripotentních kmenových buněk, mezi které patří i schopnost udržovat genomovou stabilitu neustále narušovanou transponovatelnými elementy (TE). U kmenových buněk je regulace TE zprostředkovávána především PIWI-interagujícími RNA (piRNA). Deregulované hladiny těchto krátkých RNA byly pozorovány u mnoha nádorových onemocnění, včetně nádorových kmenových buněk, což naznačuje jejich významnou úlohu v kancerogenezi. Hlubší pochopení role piRNA u GSC by tak mohlo vést jak k vývoji nových terapeutických cílů, tak k objevení nových prognostických biomarkerů u pacientů s GBM.; Glioblastoma (GBM) is the most frequent primary brain tumor of astrocytic origin. Despite great advances in molecular pathology and oncology, there is still no clinically applicable ways to classify patients according their prognosis and to overcome GBM resistance to the conventional therapy, respectively. This results in an early tumor recurrence and dismal survival of GBM patients. Biological behavior of GBM is largely linked to the presence of glioblastoma stem cells (GSCs), a cell subpopulation displaying features of pluripotent stem cells among which belongs also the ability to maintain genomic stability constantly disturbed by transposable elements (TEs). Regulation of TEs in stem cells is managed mainly by PIWI-interacting RNAs (piRNAs). Deregulated levels of these small RNAs have been also observed in many cancers including cancer stem cells suggesting their important role in cancerogenesis. Deeper understanding of piRNA roles in GSCs could led to the first step to both development of new therapeutic targets and discovery new prognostic biomarkers in GBM patients.

• Klíčová slova
• prognóza, prognosis, léčba, therapy, glioblastoma, glioblastom, PIWI-interagující RNA, glioblastomové kmenové buňky, PIWI-interacting RNA, glioblastoma stem cells,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

PIWI-interacting RNAs (piRNAs) play a crucial role in safeguarding genome integrity by silencing mobile genetic elements. From flies to humans, piRNAs originate from long single-stranded precursors encoded by genomic piRNA clusters. How piRNA clusters form to adapt to genomic invaders and evolve to maintain protection remain key outstanding questions. Here, we generate a roadmap of piRNA clusters across seven species that highlights both similarities and variations. In mammals, we identify transcriptional readthrough as a mechanism to generate piRNAs from transposon insertions (piCs) downstream of genes (DoG). Together with the well-known stress-dependent DoG transcripts, our findings suggest a molecular mechanism for the formation of piRNA clusters in response to retroviral invasion. Finally, we identify a class of dynamic piRNA clusters in humans, underscoring unique features of human germ cell biology. Our results advance the understanding of conserved principles and species-specific variations in piRNA biology and provide tools for future studies.

• MeSH
• druhová specificita MeSH
• lidé MeSH
• malá interferující RNA * metabolismus   genetika   MeSH
• myši MeSH
• Piwi-interagující RNA MeSH
• psi MeSH
• savci * genetika   MeSH
• transpozibilní elementy DNA genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Small noncoding RNAs play an important role in various disease states, including cancer. PIWI proteins, a subfamily of Argonaute proteins, and PIWI-interacting RNAs (piRNAs) were originally described as germline-specific molecules that inhibit the deleterious activity of transposable elements. However, several studies have suggested a role for the piRNA-PIWI axis in somatic cells, including somatic stem cells. Dysregulated expression of piRNAs and PIWI proteins in human tumors implies that, analogously to their roles in undifferentiated cells under physiological conditions, these molecules may be important for cancer stem cells and thus contribute to cancer progression. We provide an overview of piRNA biogenesis and critically review the evidence for the role of piRNA-PIWI axis in cancer stem cells. In addition, we examine the potential of piRNAs and PIWI proteins to become biomarkers in cancer.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear. METHODS: In this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients. RESULTS: Comparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity. CONCLUSIONS: Our findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.

• Publikační typ
• časopisecké články MeSH

Osteoarthritis (OA) is a frequent musculoskeletal disorder affecting millions of people worldwide. Despite advances in understanding the pathogenesis of OA, prognostic biomarkers or effective targeted treatment are not currently available. Research on epigenetic factors has yielded some new insights as new technologies for their detection continue to emerge. In this context, non-coding RNAs, including microRNAs, long non-coding RNAs, circular RNAs, piwi-interacting RNAs, and small nucleolar RNAs, regulate intracellular signaling pathways and biological processes that have a crucial role in the development of several diseases. In this review, we present current knowledge on the role of epigenetic factors with a focus on non-coding RNAs in the development, prediction and treatment of OA. This article is categorized under: RNA in Disease and Development > RNA in Disease.

• MeSH
• kruhová RNA MeSH
• lidé MeSH
• mikro RNA * genetika   MeSH
• osteoartróza * genetika   MeSH
• Piwi-interagující RNA MeSH
• RNA dlouhá nekódující * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

PIWI-interacting RNAs (piRNAs) and their associated PIWI clade Argonaute proteins constitute the core of the piRNA pathway. In gonadal cells, this conserved pathway is crucial for genome defense, and its main function is to silence transposable elements. This is achieved through posttranscriptional and transcriptional gene silencing. Precursors that give rise to piRNAs require specialized transcription and transport machineries because piRNA biogenesis is a cytoplasmic process. The ping-pong cycle, a posttranscriptional silencing mechanism, combines the cleavage-dependent silencing of transposon RNAs with piRNA production. PIWI proteins also function in the nucleus, where they scan for nascent target transcripts with sequence complementarity, instructing transcriptional silencing and deposition of repressive chromatin marks at transposon loci. Although studies have revealed numerous factors that participate in each branch of the piRNA pathway, the precise molecular roles of these factors often remain unclear. In this review, we summarize our current understanding of the mechanisms involved in piRNA biogenesis and function.

• MeSH
• Argonaut proteiny genetika   MeSH
• Drosophila melanogaster genetika   MeSH
• genetická transkripce * MeSH
• gonády růst a vývoj   MeSH
• malá interferující RNA biosyntéza   genetika   MeSH
• transpozibilní elementy DNA genetika   MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Background: The early detection of colon cancer is one of the main prerequisites for successful treatment and mortality reduction. Circulating PIWI-interacting RNAs (piRNA) were recently identified as novel promising biomarkers. The purpose of the study was to assess the profiles of piRNAs in blood serum of colon cancer patients with the aim to identify those with high diagnostic potential.Methods: Blood serum samples from 403 colon cancer patients and 276 healthy donors were included in this 3-phase biomarker study. Large-scale piRNA expression profiling was performed using Illumina small RNA sequencing. The diagnostic potential of selected piRNAs was further validated on independent training and validation sets of samples using RT-qPCR.Results: In total, 31 piRNAs were found to be significantly deregulated in serum of cancer patients compared with healthy donors. Based on the levels of piR-5937 and piR-28876, it was possible to differentiate between cancer patients and healthy donors with high sensitivity and specificity. Moreover, both piRNAs exhibited satisfactory diagnostic performance also in patients with stage I disease and enabled detection of colon cancer with higher sensitivity than currently used biomarkers CEA and CA19-9. Finally, the expression of analyzed piRNAs in blood restored significantly 1 month after the surgical resection.Conclusions: Based on our findings, piRNAs are abundant in human blood serum. Furthermore, their levels in colon cancer have been observed to be significantly deregulated. However, their involvement in carcinogenesis must be further established.Impact: piRNAs could serve as promising noninvasive biomarkers for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1019-28. ©2018 AACR.

• MeSH
• lidé středního věku MeSH
• lidé MeSH
• malá interferující RNA genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádory tračníku diagnóza   genetika   MeSH
• následné studie MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH