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Role of ncRNAs Classes as Biomarkers for Diagnostic and Prognosis in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 38823

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Special Issue Information

Dear Colleagues,

The discovery of miRNAs a few decades ago and of lncRNAs in the later years opened a new face of genome understanding as well as the cooperation between coding and noncoding genes in cancer. Their discovery as multiple classes of noncoding genes (snoRNA, siRNA, piRNA, circRNAs, lincRNA, asRNA and other) showed a significant role in regulating the expression of many genes in cancer pathways and progression mechanisms. Characterization and validation as potential biomarkers in different stages of cancer development from early detection to invasion and metastasis are still in its initial development, but new insights considering ncRNAs classes’ role in cancer therapy make them valuable contributors as modulators of response to different treatments. The Special Issue is devoted to all scientists that have an interest in different ncRNAs classes exploring their role in cancer diagnostic or therapy.

Prof. Ioana Berindan-Neagoe
Guest Editor

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Keywords

  • miRNAs
  • lncRNAs
  • short ncRNAs
  • snoRNAs
  • siRNA
  • piRNA
  • circRNAs
  • lincRNA
  • asRNA
  • hallmarks
  • cancer therapy
  • diagnostic
  • prognostic

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Published Papers (11 papers)

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Research

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12 pages, 1470 KiB  
Article
Evidence That Regulation of Pri-miRNA/miRNA Expression Is Not a General Rule of miPEPs Function in Humans
by Anne Prel, Christine Dozier, Jean-Philippe Combier, Serge Plaza and Arnaud Besson
Int. J. Mol. Sci. 2021, 22(7), 3432; https://doi.org/10.3390/ijms22073432 - 26 Mar 2021
Cited by 21 | Viewed by 3736
Abstract
Some miRNAs are located in RNA precursors (pri-miRNAs) annotated as long non-coding (lncRNAs) due to absence of long open reading frames (ORFs). However, recent studies have shown that some lnc pri-miRNAs encode peptides called miPEPs (miRNA-encoded peptides). Initially discovered in plants, three miPEPs [...] Read more.
Some miRNAs are located in RNA precursors (pri-miRNAs) annotated as long non-coding (lncRNAs) due to absence of long open reading frames (ORFs). However, recent studies have shown that some lnc pri-miRNAs encode peptides called miPEPs (miRNA-encoded peptides). Initially discovered in plants, three miPEPs have also been identified in humans. Herein, we found that a dozen human pri-miRNAs potentially encode miPEPs, as revealed by ribosome profiling and proteomic databases survey. So far, the only known function of plant miPEPs is to enhance the transcription of their own pri-miRNAs, thereby increasing the level and activity of their associated miRNAs and downregulating the expression of their target genes. To date, in humans, only miPEP133 was shown to promote a positive autoregulatory loop. We investigated whether other human miPEPs are also involved in regulating the expression of their miRNAs by studying miPEP155, encoded by the lnc MIR155HG, miPEP497, a sORF-encoded peptide within lnc MIR497HG, and miPEP200a, encoded by the pri-miRNA of miR-200a/miR-200b. We show that overexpression of these miPEPs is unable to impact the expression/activity of their own pri-miRNA/miRNAs in humans, indicating that the positive feedback regulation observed with plant miPEPs and human miPEP133 is not a general rule of human miPEP function. Full article
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23 pages, 4314 KiB  
Article
Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach
by Simona De Summa, Antonio Palazzo, Mariapia Caputo, Rosa Maria Iacobazzi, Brunella Pilato, Letizia Porcelli, Stefania Tommasi, Angelo Virgilio Paradiso and Amalia Azzariti
Int. J. Mol. Sci. 2021, 22(4), 2227; https://doi.org/10.3390/ijms22042227 - 23 Feb 2021
Cited by 3 | Viewed by 2900
Abstract
Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify [...] Read more.
Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify prostate cancer patients through the selection of robust long non-coding RNAs. To fulfill the purpose of the study, a bioinformatic approach focused on feature selection applied to a TCGA dataset was used. In such a way, LINC00668 and long non-coding(lnc)-SAYSD1-1, able to discriminate ERG/not-ERG subtypes, were demonstrated to be positive prognostic biomarkers in ERG-positive patients. Furthermore, we performed a comparison between mutated prostate cancer, identified as “classified”, and a group of patients with no peculiar genomic alteration, named “not-classified”. Moreover, LINC00920 lncRNA overexpression has been linked to a better outcome of the hormone regimen. Through the feature selection approach, it was found that the overexpression of lnc-ZMAT3-3 is related to low-grade patients, and three lncRNAs: lnc-SNX10-87, lnc-AP1S2-2, and ADPGK-AS1 showed, through a co-expression analysis, significant correlation values with potentially druggable pathways. In conclusion, the data mining of publicly available data and robust bioinformatic analyses are able to explore the unknown biology of malignancies. Full article
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18 pages, 3234 KiB  
Article
The Expression Profile of mRNA and tRNA Genes in Splenocytes and Neutrophils after In Vivo Delivery of Antitumor Short Hairpin RNA of Indoleamine 2,3- Dioxygenase
by Ming-Shyan Huang, Ya-Ling Hsu, I-Jeng Yeh, Kuan-Ting Liu and Meng-Chi Yen
Int. J. Mol. Sci. 2020, 21(18), 6703; https://doi.org/10.3390/ijms21186703 - 13 Sep 2020
Viewed by 2110
Abstract
RNA-based therapeutics are considered as novel treatments for human diseases. Our previous study demonstrated that treatment with short-hairpin RNA against Ido1 (IDO shRNA) suppresses tumor growth, detects Th1-bias immune responses, and elevates expression of tryptophan transfer RNA (tRNATrp) in total splenocytes. [...] Read more.
RNA-based therapeutics are considered as novel treatments for human diseases. Our previous study demonstrated that treatment with short-hairpin RNA against Ido1 (IDO shRNA) suppresses tumor growth, detects Th1-bias immune responses, and elevates expression of tryptophan transfer RNA (tRNATrp) in total splenocytes. In addition, depletion of Ly6g+ neutrophils attenuates the effect of IDO shRNA. The aim of this study was to investigate the regulatory network and the expression profile of tRNAs and other non-coding RNAs in IDO shRNA-treated spleens. The total splenocytes and magnetic bead-enriched splenic neutrophils were collected from the lung tumor bearing mice, which were treated with IDO shRNA or scramble IDO shRNA, and the collected cells were subsequently subjected to RNA sequencing. The gene ontology analysis revealed the different enrichment pathways in total splenocytes and splenic neutrophils. Furthermore, the expression of tRNA genes was identified and validated. Six isoacceptors of tRNA, with different expression patterns between total splenocytes and splenic neutrophils, were observed. In summary, our findings not only revealed novel biological processes in IDO shRNA-treated total splenocytes and splenic neutrophils, but the identified tRNAs and other non-coding RNAs may contribute to developing a novel biomarker gene set for evaluating the clinical efficiency of RNA-based cancer immunotherapies. Full article
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16 pages, 2011 KiB  
Article
Plasma-Derived miRNA-222 as a Candidate Marker for Papillary Thyroid Cancer
by Aistė Kondrotienė, Albertas Daukša, Daina Pamedytytė, Mintautė Kazokaitė, Aurelija Žvirblienė, Dalia Daukšienė, Vaida Simanavičienė, Raimonda Klimaitė, Ieva Golubickaitė, Rytis Stakaitis, Valdas Šarauskas, Rasa Verkauskienė and Birutė Žilaitienė
Int. J. Mol. Sci. 2020, 21(17), 6445; https://doi.org/10.3390/ijms21176445 - 3 Sep 2020
Cited by 17 | Viewed by 2925
Abstract
We analyzed five miRNA molecules (miR-221; miR-222; miR-146b; miR-21; miR-181b) in the plasma of patients with papillary thyroid cancer (PTC), nodular goiter (NG) and healthy controls (HC) and evaluated their diagnostic value for differentiation of PTC from NG and HC. Preoperative PTC plasma [...] Read more.
We analyzed five miRNA molecules (miR-221; miR-222; miR-146b; miR-21; miR-181b) in the plasma of patients with papillary thyroid cancer (PTC), nodular goiter (NG) and healthy controls (HC) and evaluated their diagnostic value for differentiation of PTC from NG and HC. Preoperative PTC plasma miRNA expression (n = 49) was compared with plasma miRNA in the HC group (n = 57) and patients with NG (n = 23). It was demonstrated that miR-221; miR-222; miR-146b; miR-21 and miR-181b were overexpressed in preoperative PTC plasma samples compared to HC (p < 0.0001; p < 0.0001; p < 0.0001; p < 0.0001; p < 0.002; respectively). The upregulation in tumor tissue of these miRNAs was consistent with The Cancer Genome Atlas Thyroid Carcinoma dataset. A significant decrease in miR-21; miR-221; miR-146b and miR-181b expression was observed in the plasma of PTC patients after total thyroidectomy (p = 0.004; p = 0.001; p = 0.03; p = 0.036; respectively). The levels of miR-222 were significantly higher in the preoperative PTC compared to the NG group (p = 0.004). ROC curve (receiver operating characteristic curve) analysis revealed miR-222 as a potential marker in distinguishing PTC from NG (AUC 0.711; p = 0.004). In conclusion; circulating miR-222 profiles might be useful in discriminating PTC from NG. Full article
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16 pages, 1887 KiB  
Article
Discriminating miRNA Profiles between Endometrioid Well- and Poorly-Differentiated Tumours and Endometrioid and Serous Subtypes of Endometrial Cancers
by Lenka Kalinkova, Karol Kajo, Miloslav Karhanek, Lenka Wachsmannova, Peter Suran, Iveta Zmetakova and Ivana Fridrichova
Int. J. Mol. Sci. 2020, 21(17), 6071; https://doi.org/10.3390/ijms21176071 - 23 Aug 2020
Cited by 10 | Viewed by 3931
Abstract
The discrimination of different subtypes of endometrial carcinoma (EC) is frequently problematic when using the current histomorphological classification; therefore, new markers for this differentiation are needed. Here, we examined differences in miRNA expression between well- and poorly-differentiated (grades 1 and 3) endometrioid endometrial [...] Read more.
The discrimination of different subtypes of endometrial carcinoma (EC) is frequently problematic when using the current histomorphological classification; therefore, new markers for this differentiation are needed. Here, we examined differences in miRNA expression between well- and poorly-differentiated (grades 1 and 3) endometrioid endometrial carcinoma (EEC) and between EEC and serous endometrial carcinoma (SEC). The expression of 84 tumour-suppressor miRNAs was analysed by real-time polymerase chain reactions in 62 EC and 20 non-neoplastic endometrial specimens. The potential functions of the differentially expressed miRNAs were determined by bioinformatics analyses. The expression of let-7c-5p, miR-125b-5p, miR-23b-3p, and miR-99a-5p in grade 3 EEC was decreased compared to grade 1 EEC. To discriminate between EEC and SEC, let-7g-5p, miR-195-5p, miR-34a-5p, and miR-497-5p expression was significantly downregulated in SEC. In bioinformatic analyses, miRNAs that could discriminate grade 1 from grade 3 mainly targeted genes involved in PI3K-AKT signaling, whereas miRNAs that could discriminate EEC from SEC targeted genes involved in several signaling pathways, but mainly MAPK signaling. Taken collectively, our results indicate that the activation of certain signaling pathways can be useful in the molecular characterization of EEC and SEC. Full article
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Review

Jump to: Research

27 pages, 687 KiB  
Review
Measurements Methods for the Development of MicroRNA-Based Tests for Cancer Diagnosis
by Francesca Precazzini, Simone Detassis, Andrea Selenito Imperatori, Michela Alessandra Denti and Paola Campomenosi
Int. J. Mol. Sci. 2021, 22(3), 1176; https://doi.org/10.3390/ijms22031176 - 25 Jan 2021
Cited by 39 | Viewed by 5608
Abstract
Studies investigating microRNAs as potential biomarkers for cancer, immune-related diseases, or cardiac pathogenic diseases, among others, have exponentially increased in the last years. In particular, altered expression of specific miRNAs correlates with the occurrence of several diseases, making these molecules potential molecular tools [...] Read more.
Studies investigating microRNAs as potential biomarkers for cancer, immune-related diseases, or cardiac pathogenic diseases, among others, have exponentially increased in the last years. In particular, altered expression of specific miRNAs correlates with the occurrence of several diseases, making these molecules potential molecular tools for non-invasive diagnosis, prognosis, and response to therapy. Nonetheless, microRNAs are not in clinical use yet, due to inconsistencies in the literature regarding the specific miRNAs identified as biomarkers for a specific disease, which in turn can be attributed to several reasons, including lack of assay standardization and reproducibility. Technological limitations in circulating microRNAs measurement have been, to date, the biggest challenge for using these molecules in clinical settings. In this review we will discuss pre-analytical, analytical, and post-analytical challenges to address the potential technical biases and patient-related parameters that can have an influence and should be improved to translate miRNA biomarkers to the clinical stage. Moreover, we will describe the currently available methods for circulating miRNA expression profiling and measurement, underlining their advantages and potential pitfalls. Full article
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23 pages, 1735 KiB  
Review
Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy
by Alexandru Tirpe, Diana Gulei, George Razvan Tirpe, Andreea Nutu, Alexandru Irimie, Paola Campomenosi, Laura Ancuta Pop and Ioana Berindan-Neagoe
Int. J. Mol. Sci. 2020, 21(21), 8002; https://doi.org/10.3390/ijms21218002 - 27 Oct 2020
Cited by 12 | Viewed by 3412
Abstract
GLOBOCAN 2018 identified lung cancer as the leading oncological pathology in terms of incidence and mortality rates. Angiogenesis is a key adaptive mechanism of numerous malignancies that promotes metastatic spread in view of the dependency of cancer cells on nutrients and oxygen, favoring [...] Read more.
GLOBOCAN 2018 identified lung cancer as the leading oncological pathology in terms of incidence and mortality rates. Angiogenesis is a key adaptive mechanism of numerous malignancies that promotes metastatic spread in view of the dependency of cancer cells on nutrients and oxygen, favoring invasion. Limitation of the angiogenic process could significantly hamper the disease advancement through starvation of the primary tumor and impairment of metastatic spread. This review explores the basic molecular mechanisms of non-small cell lung cancer (NSCLC) angiogenesis, and discusses the influences of the key proangiogenic factors—the vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (FGF2), several matrix metalloproteinases (MMPs—MMP-2, MMP-7, MMP-9) and hypoxia—and the therapeutic implications of microRNAs (miRNAs, miRs) throughout the entire process, while also providing critical reviews of a number of microRNAs, with a focus on miR-126, miR-182, miR-155, miR-21 and let-7b. Finally, current conventional NSCLC anti-angiogenics—bevacizumab, ramucirumab and nintedanib—are briefly summarized through the lens of evidence-based medicine. Full article
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30 pages, 1340 KiB  
Review
Non-Coding RNAs in Brain Tumors, the Contribution of lncRNAs, circRNAs, and snoRNAs to Cancer Development—Their Diagnostic and Therapeutic Potential
by Julia Latowska, Adriana Grabowska, Żaneta Zarębska, Konrad Kuczyński, Bogna Kuczyńska and Katarzyna Rolle
Int. J. Mol. Sci. 2020, 21(19), 7001; https://doi.org/10.3390/ijms21197001 - 23 Sep 2020
Cited by 33 | Viewed by 4219
Abstract
Brain tumors are one of the most frightening ailments that afflict human beings worldwide. They are among the most lethal of all adult and pediatric solid tumors. The unique cell-intrinsic and microenvironmental properties of neural tissues are some of the most critical obstacles [...] Read more.
Brain tumors are one of the most frightening ailments that afflict human beings worldwide. They are among the most lethal of all adult and pediatric solid tumors. The unique cell-intrinsic and microenvironmental properties of neural tissues are some of the most critical obstacles that researchers face in the diagnosis and treatment of brain tumors. Intensifying the search for potential new molecular markers in order to develop new effective treatments for patients might resolve this issue. Recently, the world of non-coding RNAs (ncRNAs) has become a field of intensive research since the discovery of their essential impact on carcinogenesis. Some of the most promising diagnostic and therapeutic regulatory RNAs are long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs). Many recent reports indicate the important role of these molecules in brain tumor development, as well as their implications in metastasis. In the following review, we summarize the current state of knowledge about regulatory RNAs, namely lncRNA, circRNAs, and snoRNAs, and their impact on the development of brain tumors in children and adults with particular emphasis on malignant primary brain tumors—gliomas and medulloblastomas (MB). We also provide an overview of how these different ncRNAs may act as biomarkers in these tumors and we present their potential clinical implications. Full article
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15 pages, 1064 KiB  
Review
Circular RNAs in Hematopoiesis with a Focus on Acute Myeloid Leukemia and Myelodysplastic Syndrome
by Michaela Dostalova Merkerova, Zdenek Krejcik, Katarina Szikszai and David Kundrat
Int. J. Mol. Sci. 2020, 21(17), 5972; https://doi.org/10.3390/ijms21175972 - 19 Aug 2020
Cited by 6 | Viewed by 2465
Abstract
Circular RNAs (circRNAs) constitute a recently recognized group of noncoding transcripts that function as posttranscriptional regulators of gene expression at a new level. Recent developments in experimental methods together with rapidly evolving bioinformatics approaches have accelerated the exploration of circRNAs. The differentiation of [...] Read more.
Circular RNAs (circRNAs) constitute a recently recognized group of noncoding transcripts that function as posttranscriptional regulators of gene expression at a new level. Recent developments in experimental methods together with rapidly evolving bioinformatics approaches have accelerated the exploration of circRNAs. The differentiation of hematopoietic stem cells into a broad spectrum of specialized blood lineages is a tightly regulated process that depends on a multitude of factors, including circRNAs. However, despite the growing number of circRNAs described to date, the roles of the majority of them in hematopoiesis remain unknown. Given their stability and disease-specific expression, circRNAs have been acknowledged as novel promising biomarkers and therapeutic targets. In this paper, the biogenesis, characteristics, and roles of circRNAs are reviewed with an emphasis on their currently recognized or presumed involvement in hematopoiesis, especially in acute myeloid leukemia and myelodysplastic syndrome. Full article
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13 pages, 737 KiB  
Review
Prognostic and Clinicopathological Significance of MiR-155 in Breast Cancer: A Systematic Review
by Anna Maria Grimaldi, Silvia Nuzzo, Gerolama Condorelli, Marco Salvatore and Mariarosaria Incoronato
Int. J. Mol. Sci. 2020, 21(16), 5834; https://doi.org/10.3390/ijms21165834 - 14 Aug 2020
Cited by 20 | Viewed by 2636
Abstract
There is an unmet need for novel non-invasive prognostic molecular tumour markers for breast cancer (BC). Accumulating evidence shows that miR-155 plays a pivotal role in tumorigenesis. Generally, miR-155 is considered an oncogenic miRNA promoting tumour growth, angiogenesis and aggressiveness of BC. Therefore, [...] Read more.
There is an unmet need for novel non-invasive prognostic molecular tumour markers for breast cancer (BC). Accumulating evidence shows that miR-155 plays a pivotal role in tumorigenesis. Generally, miR-155 is considered an oncogenic miRNA promoting tumour growth, angiogenesis and aggressiveness of BC. Therefore, many researchers have focused on its use as a prognostic biomarker and therapeutic target. However, its prognostic value for BC patients remains controversial. To address this issue, the present systematic review aims to summarize the available evidence and give a picture of a prognostic significance of miR-155 in BC pathology. All eligible studies were searched on PubMed and EMBASE databases through various search strategies. Starting from 289 potential eligible records, data were examined from 28 studies, comparing tissue and circulating miR-155 expression levels with clinicopathological features and survival rates in BC patients. We discuss the pitfalls and challenges that need to be assessed to understand the power of miR-155 to respond to real clinical needs, highlighting the consistency, robustness or lack of results obtained to sate in translating this molecule to clinical practice. Our paper suggests that the prognostic role of miR-155 in the management of BC needs to be further verified. Full article
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12 pages, 2192 KiB  
Review
YRNAs and YRNA-Derived Fragments as New Players in Cancer Research and Their Potential Role in Diagnostics
by Kacper Guglas, Iga Kołodziejczak, Tomasz Kolenda, Magda Kopczyńska, Anna Teresiak, Joanna Sobocińska, Renata Bliźniak and Katarzyna Lamperska
Int. J. Mol. Sci. 2020, 21(16), 5682; https://doi.org/10.3390/ijms21165682 - 8 Aug 2020
Cited by 26 | Viewed by 3870
Abstract
YRNAs are a type of short, noncoding RNAs. A total of four different transcripts can be distinguished, which are YRNA1, YRNA3, YRNA4 and YRNA5. All YRNAs are relatively small, made up of about 100 nucleotides each. YRNAs are characterized by [...] Read more.
YRNAs are a type of short, noncoding RNAs. A total of four different transcripts can be distinguished, which are YRNA1, YRNA3, YRNA4 and YRNA5. All YRNAs are relatively small, made up of about 100 nucleotides each. YRNAs are characterized by a stem-loop structure and each part of that structure carries a different function. YRNAs are transcribed in the nucleus by RNA polymerase III. Then, the YRNA molecule is bound to the polyuridine tail of the La protein responsible for both its nuclear retention and protection from degradation. They also bind to the Ro60 protein, making the molecule more stable. In turn, YRNA-derived small RNAs (YsRNAs) are a class of YRNAs produced in apoptotic cells as a result of YRNA degradation. This process is performed by caspase-3-dependent pathways that form two groups of YsRNAs, with lengths of either approximately 24 or 31 nucleotides. From all four YRNA transcripts, 75 well-described pseudogenes are generated as a result of the mutation. However, available data indicates the formation of up to 1000 pseudogenes. YRNAs and YRNA-derived small RNAs may play a role in carcinogenesis due to their altered expression in cancers and influence on cell proliferation and inflammation. Nevertheless, our knowledge is still limited, and more research is required. The main aim of this review is to describe the current state of knowledge about YRNAs, their function and contribution to carcinogenesis, as well as their potential role in cancer diagnostics. To confirm the promising potential of YRNAs and YRNA-derived fragments as biomarkers, their significant role in several tumor types was taken into consideration. Full article
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