Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. METHODS: In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. RESULTS: Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR. CONCLUSIONS: These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.
- Publication type
- Journal Article MeSH
Circular RNAs (circRNAs) have played an essential role in cancer development. This study aimed to illustrate the impact and potential mechanism of circRACGAP1 action in NSCLC development. The expression patterns of circRACGAP1, miR-1296, and CDK2 in NSCLC tissues and cell lines were analysed by RT-qPCR. The function of circRACGAP1 in NSCLC cell proliferation and apoptosis was investigated using the CCK-8 assay, flow cytometry, TUNEL staining, and Western blot. The interaction among circRACGAP1, miR-1296, and CDK2 was clarified by dual-luciferase reporter assay while the correlation was confirmed by the Pearson correlation coefficient. The expression of circRACGAP1 and CDK2 was up-regulated in NSCLC tissues, while the expression of miR-1296 was down-regulated. Cell function studies further revealed that circRACGAP1 could promote NSCLC cell proliferation, accelerate the cell cycle process, up-regulate B-cell lymphoma 2 (Bcl2) expression, and down-regulate Bcl2-associated X (Bax) expression. miR-1296 was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-1296 directly targeted the 3'-UTR of CDK2 to regulate proliferation and apoptosis of NSCLC cells. Additionally, the dual-luciferase reporter assay and Pearson correlation coefficient analysis proved that circRACGAP1 acted in NSCLC cells by negatively regulating miR-1296 expression and positively regulating CDK2 expression. In summary, our study revealed that circRACGAP1 promoted NSCLC cell proliferation by regulating the miR-1296/CDK2 pathway, providing potential diagnostic and therapeutic targets for NSCLC.
- MeSH
- Apoptosis * genetics MeSH
- Cyclin-Dependent Kinase 2 * metabolism genetics MeSH
- RNA, Circular * genetics metabolism MeSH
- Humans MeSH
- MicroRNAs * genetics metabolism MeSH
- Cell Line, Tumor MeSH
- Lung Neoplasms * genetics pathology metabolism MeSH
- Carcinoma, Non-Small-Cell Lung * genetics pathology metabolism MeSH
- Cell Proliferation * genetics MeSH
- GTPase-Activating Proteins genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Signal Transduction genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.
- MeSH
- Extracellular Vesicles * metabolism MeSH
- RNA, Circular genetics metabolism MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- Cell Communication MeSH
- MicroRNAs genetics metabolism MeSH
- Tumor Microenvironment * MeSH
- Neoplasms * pathology genetics metabolism MeSH
- RNA, Long Noncoding genetics MeSH
- RNA genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington's disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. While an IRES-like motif was predicted in circHTT(2,3,4,5,6), the circRNA does not appear to be translated in adult mouse brain tissue. Nonetheless, a modest, but consistent fraction of circHtt(2,3,4,5,6) associates with the 40S ribosomal subunit, suggesting a possible role in the regulation of protein translation. Finally, circHtt(2,3,4,5,6) overexpression experiments in HD-relevant STHdh striatal cells revealed its ability to modulate CAG expansion-driven cellular defects in cell-to-substrate adhesion, thus uncovering an unconventional modifier of HD pathology.
- Publication type
- Journal Article MeSH
Východiska: Spinocelulární karcinom dutiny ústní (oral squamous cell carcinoma – OSCC) je nejběžnějším typem zhoubných nádorů v oblasti hlavy a krku. Je známo, že cirkulární RNA (circRNA) hraje důležitou roli v karcinogenezi různých typů zhoubných nádorů. Role circRNA při OSCC však zůstává nejasná. Materiál a metody: Byly získány tkáně OSCC a přilehlé normální tkáně k detekci exprese circRNA sekvenováním nové generace (next generation sequencing – NGS) a byly vybrány tkáně OSCC k ověření circRNAs různého významu pomocí kvantitativní polymerázové řetězové reakce s reverzní transkriptázou (reverse transcriptase-quantitative polymerase chain reaction – RT-qPCR). Pro další zkoumání role hsa-circ-0006203 – hsa-circ-0004872 byl vytvořen design primeru a byla provedena RT-PCR. Hladiny exprese byly detekovány pomocí RT-qPCR. Výsledky: Výsledky NGS ukázaly, že u OSCC byly výrazně exprimovány circRNA, přičemž dvě circRNAs byly exprimovány výrazně odlišným způsobem. hsa-circ-0006203 – hsa-circ-0004872 byly ve vzorcích tkáně OSCC výrazně downregulována, což statisticky korelovalo s jejich patologickou diferenciací. Závěr: Souhrnně lze říci, že výsledky prezentované studie odhalily zvýšené množství circRNA ve tkáních OSCC a pokud je nám známo, náš tým jako první zkoumal regulační roli sítě hsa-circ-0006203 – hsa-circ-0004872 u OSCC. Výsledky ukázaly, že hsa-circ-0006203 – hsa-circ-0004872 může být případným biomarkerem OSCC.
Background: Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck region. The circular RNA (circRNA) is known to serve an important role in the carcinogenesis of different types of cancer. However, the circRNA role of OSCC remains unclear. Material and methods: OSCC tissues and adjacent normal tissues were obtained to detect circRNAs expression by the next generation sequencing (NGS), and OSCC tissues were selected to verify the differentially significant circRNAs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To further investigate the role of hsa-circ-0006203 – hsa-circ-0004872, the primer design and RT-PCR were performed. The expression levels were detected by RT-qPCR. Results: The NGS results demonstrated that circRNAs were abundantly expressed in OSCC, and two circRNAs were significantly differentially expressed. hsa-circ-0006203 – hsa-circ-0004872 were significantly downregulated in OSCC tissue samples and was statistically correlated with pathological differentiation. Conclusion: In summary, the results of the present study revealed that OSCC tissues have abundant circRNAs and, to the best of our knowledge, it was our team who firstly explore the regulatory role of the hsa-circ-0006203 – hsa-circ-0004872 network in OSCC. The results indicated that hsa-circ-0006203 – hsa-circ-0004872 may be a potential biomarker for OSCC.
- Keywords
- hsa-circ-0006203, hsa-circ-0004872,
- MeSH
- Clinical Studies as Topic MeSH
- RNA, Circular MeSH
- Humans MeSH
- Biomarkers, Tumor MeSH
- Mouth Neoplasms * diagnosis genetics MeSH
- Check Tag
- Humans 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
- RNA, Circular MeSH
- Humans MeSH
- MicroRNAs * genetics MeSH
- Osteoarthritis * genetics MeSH
- Piwi-Interacting RNA MeSH
- RNA, Long Noncoding * genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.
- MeSH
- Leukemia, Myeloid, Acute * MeSH
- Phosphoproteins genetics MeSH
- RNA, Circular genetics MeSH
- Humans MeSH
- Mutation genetics MeSH
- Myelodysplastic Syndromes * genetics MeSH
- RNA Splicing Factors genetics MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Východiska: Cílem předkládané studie je získat vhled do patogenéze karcinomu plic (lung cancer – LC) a poskytnout nové biomarkery pro LC, a to vytvořením sítě regulačních cirkulárních (circ) RNA-micro (mi) RNA-mRNA. Materiál a metody: Pomocí R programovacího jazyku Limma byla prověřena data o vysokokapacitním (high-throughput) sekvenování circRNAs, miRNAs a mRNAs souvisejících s LC, která byla vzata z databáze Gene Expression Omnibus (GEO) a data o rozdílné expresi circRNAs, miRNAs a mRNAs. K vybudování sítě ceRNA byly použity páry circRNA-miRNA a miRNA-mRNA. Funkce rozdílné exprese circRNAs byly objasněny tak, že byla provedena analýza funkčního obohacení genů pomocí databází GO a KEGG. Vybrané prognostické geny pro LC byly navíc ověřeny v tkáňových čipech a pomocí imunohistochemie (IHC). Výsledky: V LC bylo celkem identifikováno 20 downregulovaných circRNAs, 55 upregulovaných miRNAs a 243 downregulovaných mRNA. Nakonec byla vytvořena síť circRNA-miRNA-mRNA ceRNA, která se skládala ze dvou circRNAs, dvou miRNAs a dvou mRNAs. Jak vyplynulo z analýzy založené na veřejných databázích a IHC, různé geny (tj. FXYD1 a SEMA5A) v této síti fungovaly jako prognostické faktory při LC. Provedením IHC a analýzami přežití bylo potvrzeno, že exprese FXYD1 a SEMA5A při LC byla downregulována a tato exprese odrážela vztah k celkovému přežití pacientů s LC. Závěry: Tato studie představuje nové vhledy do role circRNAs při rozvoji LC skrze mechanizmus ceRNA. Identifikace genů FXYD1 a SEMA5A by mohla fungovat jako nový a nezbytný prognostický ukazatel LC.
Background: The presented study aimed to gain insights into the pathogenesis of lung cancer (LC) and provide novel biomarkers for LC by building a regulatory circular (circ) RNA-micro (mi) RNA-mRNA network. Materials and methods: High-throughput sequencing data of circRNAs, miRNAs and mRNAs related to LC originated from GEO (Gene Expression Omnibus) database, and the differential expressions of circRNAs, miRNAs and mRNAs were screened with R language Limma. The circRNA-miRNA and miRNA-mRNA pairs were used to build the ceRNA network. The functions of differential expression circRNAs were elucidated by performing the functional enrichment analysis on GO and KEGG. Furthermore, the selected LC prognostic genes were verified by tissue chips and immunohistochemistry (IHC). Results: On the whole, 20 downregulated circRNAs, 55 upregulated miRNAs and 243 downregulated mRNAs were identified in LC. Lastly, a circRNA-miRNA-mRNA ceRNA network was built, which was composed of 2 circRNAs, 2 miRNAs, and 2 mRNAs. As indicated from the analysis based on public databases and IHC, the differential genes (i.e., FXYD1 and SEMA5A) in this network acted as LC prognostic factors. As confirmed by performing IHC and survival analyses, FXYD1 and SEMA5A expressions in LC were downregulated, and their expressions displayed a relationship to the overall survival (OS) of LC cases. Conclusions: This study presents novel insights into the role of circRNAs in the development of LC via the ceRNA mechanism. The identified FXYD1 and SEMA5A gene could act as novel and vital LC prognostic indicators.
As the current staging and grading systems are not sufficient to stratify patients for therapy and predict the outcome of the disease, there is an urgent need to understand cancer in its complexity. The mutual relationship between tumour and immune or stromal cells leads to rapid evolution and subsequent genetic and epigenetic changes. Immunoscore has been introduced as a diagnostic tool for colorectal cancer (CRC) only recently, emphasising the role of the specific tumor microenvironment in patient's prognosis and overall outcome. Despite the fact that non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), cannot be translated into proteins, they significantly affect cell's transcriptome and translatome. miRNA binding to mRNA efficiently blocks its translation and leads to mRNA destruction. On the other hand, miRNAs can be bound by lncRNAs or circular RNAs (circRNAs), which prevents them from interfering with translation. In this way, ncRNAs create a multi-step network that regulates the cell's translatome. ncRNAs are also shed by the cell as exogenous RNAs and they are also found in exosomes, suggesting their role in intercellular communication. Hence, these mechanisms affect the tumor microenvironment as much as protein signal molecules. In this review, we provide an insight into the current knowledge of the microenvironment, lncRNAs', and miRNAs' interplay. Understanding mechanisms that underlie the evolution of a tissue as complex as a tumour is crucial for the future success in therapy.
- Publication type
- Journal Article MeSH
- Review MeSH
