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microRNAs and Other Non-Coding RNAs in Human Diseases

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 September 2016) | Viewed by 86866

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Prof. Dr. George A. Calin

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Department of Translational Molecular Pathology, Center for RNA Interference and Non-Coding RNAs, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: non-coding RNA; microRNA; cancer; metastasis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Muller Fabbri

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Guest Editor

Children's Hospital Los Angeles, Children’s Center for Cancer and Blood Diseases, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Interests: inflammation; tumor microenvironment; blood diseases; immune cells

Special Issue Information

Dear Colleagues,

One of the most unexpected and fascinating discoveries in oncology over the past few years is the interplay between abnormalities in protein-coding genes and noncoding RNAs (ncRNAs) that is causally involved in cancer initiation, progression, and dissemination. MicroRNAs (miRNAs), small regulatory ncRNAs, are involved in the Pathogenesis of all types of human cancers, as well as in many other human disorders, mainly via dysregulation of expression of cancer genes. Increasing evidence shows that miRNAs can work as oncogenes (activating malignant potential) or tumor suppressors (inhibiting malignant potential). Understanding the roles of miRNAs and other ncRNAs in diseases is not only uncovering a new layer of gene regulation but also providing new markers for improved diagnosis and prognosis, as well as novel therapeutic options for patients. In a single issue of Genes in Spring of 2017, we would like to focus on the roles of microRNAs and long non-coding RNAs in human diseases, highlighting what is already known about their function and describing the challenges for the near future development of biomarkers and new Therapeutics.

Prof. Dr. George A Calin
Dr. Muller Fabbri
Guest Editors

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Published Papers (13 papers)

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2104 KiB

Open AccessArticle

MicroRNA Expression Profile Identifies High Grade, Non-Muscle-Invasive Bladder Tumors at Elevated Risk to Progress to an Invasive Phenotype

by Sara M. Lenherr, Sheaumei Tsai, Brasil Silva Neto, Travis B. Sullivan, Cara B. Cimmino, Tanya Logvinenko, Jason Gee, Wei Huang, John A. Libertino, Ian C. Summerhayes and Kimberly M. Rieger-Christ

Genes 2017, 8(2), 77; https://doi.org/10.3390/genes8020077 - 17 Feb 2017

Cited by 21 | Viewed by 5258

Abstract

The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

Integrative miRNA-Gene Expression Analysis Enables Refinement of Associated Biology and Prediction of Response to Cetuximab in Head and Neck Squamous Cell Cancer

by Loris De Cecco, Marco Giannoccaro, Edoardo Marchesi, Paolo Bossi, Federica Favales, Laura D. Locati, Lisa Licitra, Silvana Pilotti and Silvana Canevari

Genes 2017, 8(1), 35; https://doi.org/10.3390/genes8010035 - 14 Jan 2017

Cited by 25 | Viewed by 6234

Abstract

This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square–discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients. Gene set enrichment analysis identified a significant correlation between the miRNA first-component and EGFR signaling, keratinocyte differentiation, and p53. Another significant correlation was identified between the second component and RAS, NOTCH, immune/inflammatory response, epithelial–mesenchymal transition (EMT), and angiogenesis pathways. Regularized canonical correlation analysis of sPLS-DA miRNA and gene data combined with the MAGIA2 web-tool highlighted 16 miRNAs and 84 genes that were interconnected in a total of 245 interactions. After feature selection by a smoothed t-statistic support vector machine, we identified three miRNAs and five genes in the miRNA-gene network whose expression result was the most relevant in predicting PFS (Area Under the Curve, AUC = 0.992). Overall, using a well-defined clinical setting and up-to-date bioinformatics tools, we are able to give the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to the refinement of the biology behind a predictive model. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

miR-203 and miR-320 Regulate Bone Morphogenetic Protein-2-Induced Osteoblast Differentiation by Targeting Distal-Less Homeobox 5 (Dlx5)

by Navya Laxman, Hans Mallmin, Olle Nilsson and Andreas Kindmark

Genes 2017, 8(1), 4; https://doi.org/10.3390/genes8010004 - 23 Dec 2016

Cited by 35 | Viewed by 6087

Abstract

MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer

by Sara Terreri, Montano Durso, Vincenza Colonna, Alessandra Romanelli, Daniela Terracciano, Matteo Ferro, Sisto Perdonà, Luigi Castaldo, Ferdinando Febbraio, Filomena De Nigris and Amelia Cimmino

Genes 2016, 7(12), 127; https://doi.org/10.3390/genes7120127 - 14 Dec 2016

Cited by 27 | Viewed by 5286

Abstract

MicroRNAs (miRNAs) are highly conserved elements in mammals, and exert key regulatory functions. Growing evidence shows that miRNAs can interact with another class of non-coding RNAs, so-called transcribed ultraconserved regions (T-UCRs), which take part in transcriptional, post-transcriptional and epigenetic regulation processes. We report here the interaction of miRNAs and T-UCRs as a network modulating the availability of these non-coding RNAs in bladder cancer cells. In our cell system, antagomiR-596 increased the expression of T-UCR 201+. Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors. In addition, we identify the polycomb protein Yin Yang 1 (YY1) as mediator of binding between miR-596 and T-UCR 8+. These new findings describe for the first time a network between T-UCRs, miRNAs and YY1 protein, highlighting the existence of an additional layer of gene expression regulation. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

microRNA Expression in Sentinel Nodes from Progressing Melanoma Patients Identifies Networks Associated with Dysfunctional Immune Response

by Viviana Vallacchi, Chiara Camisaschi, Matteo Dugo, Elisabetta Vergani, Paola Deho, Ambra Gualeni, Veronica Huber, Annunziata Gloghini, Andrea Maurichi, Mario Santinami, Marialuisa Sensi, Chiara Castelli, Licia Rivoltini and Monica Rodolfo

Genes 2016, 7(12), 124; https://doi.org/10.3390/genes7120124 - 14 Dec 2016

Cited by 9 | Viewed by 5604

Abstract

Sentinel node biopsy (SNB) is a main staging biomarker in melanoma and is the first lymph node to drain the tumor, thus representing the immunological site where anti-tumor immune dysfunction is established and where potential prognostic immune markers can be identified. Here we analyzed microRNA (miR) profiles in archival tumor-positive SNBs derived from melanoma patients with different outcomes and performed an integrated analysis of transcriptional data to identify deregulated immune signaling networks. Twenty-six miRs were differentially expressed in melanoma-positive SNB samples between patients with disease progression and non-progressing patients, the majority being previously reported in the regulation of immune responses. A significant variation in miR expression levels was confirmed in an independent set of SNB samples. Integrated information from genome-wide transcriptional profiles and in vitro assessment in immune cells led to the identification of miRs associated with the regulation of the TNF receptor superfamily member 8 (TNFRSF8) gene encoding the CD30 receptor, a marker increased in lymphocytes of melanoma patients with progressive disease. These findings indicate that miRs are involved in the regulation of pathways leading to immune dysfunction in the sentinel node and may provide valuable markers for developing prognostic molecular signatures for the identification of stage III melanoma patients at risk of recurrence. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessCommunication

Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer’s Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7)

by Yuhai Zhao, Peter N. Alexandrov, Vivian Jaber and Walter J. Lukiw

Genes 2016, 7(12), 116; https://doi.org/10.3390/genes7120116 - 05 Dec 2016

Cited by 249 | Viewed by 9631

Abstract

Our understanding of the highly specialized functions for small non-coding single-stranded RNA (ssRNA) in the transcriptome of the human central nervous system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently discovered class of ssRNA enriched in the brain and retina, are extremely stable and intrinsically resilient to degradation by exonuclease. Conventional methods of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation requiring free ribonucleotide ends may have considerably underestimated the quantity and significance of CNS circRNA in the CNS. Highly-specific small ssRNAs, such as the ~23 nucleotide (nt) Homo sapien microRNA-7 (hsa-miRNA-7; chr 9q21.32), are not only abundant in the human limbic system but are, in addition, associated with a ~1400 nt circRNA for miRNA-7 (ciRS-7) in the same anatomical region. Structurally, ciRS-7 contains about ~70 tandem anti-miRNA-7 sequences and acts as an endogenous, anti-complementary miRNA-7 “sponge” that attracts, binds, and, hence, quenches, natural miRNA-7 functions. Using a combination of DNA and miRNA array technologies, enhanced LED-Northern and Western blot hybridization, and the magnesium-dependent exoribonuclease and circRNA-sensitive probe RNaseR, here we provide evidence of a significantly misregulated ciRS-7-miRNA-7-UBE2A circuit in sporadic Alzheimer’s disease (AD) neocortex (Brodmann A22) and hippocampal CA1. Deficits in ciRS-7-mediated “sponging events”, resulting in excess ambient miRNA-7 appear to drive the selective down-regulation in the expression of miRNA-7-sensitive mRNA targets, such as that encoding the ubiquitin conjugating enzyme E2A (UBE2A; chr Xq24). UBE2A, which normally serves as a central effector in the ubiquitin-26S proteasome system, coordinates the clearance of amyloid peptides via proteolysis, is known to be depleted in sporadic AD brain and, hence, contributes to amyloid accumulation and the formation of senile plaque deposits. Dysfunction of circRNA-miRNA-mRNA regulatory systems appears to represent another important layer of epigenetic control over pathogenic gene expression programs in the human CNS that are targeted by the sporadic AD process. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

In Silico Characterization of miRNA and Long Non-Coding RNA Interplay in Multiple Myeloma

by Domenica Ronchetti, Martina Manzoni, Katia Todoerti, Antonino Neri and Luca Agnelli

Genes 2016, 7(12), 107; https://doi.org/10.3390/genes7120107 - 29 Nov 2016

Cited by 14 | Viewed by 6243

Abstract

The identification of deregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. In addition, the cross-regulation between lncRNAs and miRNAs has begun to emerge, and theoretical and experimental studies have demonstrated the competing endogenous RNA (ceRNA) activity of lncRNAs as natural miRNA decoys in pathophysiological conditions, including cancer. Currently, information concerning lncRNA and miRNA interplay in MM is virtually absent. Herein, we investigated in silico the lncRNA and miRNA relationship in a representative datasets encompassing 95 MM and 30 plasma cell leukemia patients at diagnosis and in four normal controls, whose expression profiles were generated by a custom annotation pipeline to detect specific lncRNAs. We applied target prediction analysis based on miRanda and RNA22 algorithms to 235 lncRNAs and 459 miRNAs selected with a potential pivotal role in the pathology of MM. Among pairs that showed a significant correlation between lncRNA and miRNA expression levels, we identified 11 lncRNA–miRNA relationships suggestive of a novel ceRNA network with relevance in MM. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessArticle

Identification of Long Non‐Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors

by Ehsan Malek, Byung‐Gyu Kim and James J. Driscoll

Genes 2016, 7(10), 84; https://doi.org/10.3390/genes7100084 - 06 Oct 2016

Cited by 16 | Viewed by 5140

Abstract

While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose‐limiting toxicities and the inevitable emergence of drug resistance limit their long‐term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy‐induced, which accounts for the majority of tumor relapses and MM‐related deaths. Non‐coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non‐coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome‐wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug‐sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI‐resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Review

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Open AccessReview

Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

by Duncan Ayers and Jo Vandesompele

Genes 2017, 8(3), 95; https://doi.org/10.3390/genes8030095 - 03 Mar 2017

Cited by 95 | Viewed by 9641

Abstract

Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessReview

Non-Coding RNAs in Lung Cancer: Contribution of Bioinformatics Analysis to the Development of Non-Invasive Diagnostic Tools

by Meik Kunz, Beat Wolf, Harald Schulze, David Atlan, Thorsten Walles, Heike Walles and Thomas Dandekar

Genes 2017, 8(1), 8; https://doi.org/10.3390/genes8010008 - 26 Dec 2016

Cited by 27 | Viewed by 7757

Abstract

Lung cancer is currently the leading cause of cancer related mortality due to late diagnosis and limited treatment intervention. Non-coding RNAs are not translated into proteins and have emerged as fundamental regulators of gene expression. Recent studies reported that microRNAs and long non-coding RNAs are involved in lung cancer development and progression. Moreover, they appear as new promising non-invasive biomarkers for early lung cancer diagnosis. Here, we highlight their potential as biomarker in lung cancer and present how bioinformatics can contribute to the development of non-invasive diagnostic tools. For this, we discuss several bioinformatics algorithms and software tools for a comprehensive understanding and functional characterization of microRNAs and long non-coding RNAs. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessReview

Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases

by Nayra Soares do Amaral, Natalia Cruz e Melo, Beatriz De Melo Maia and Rafael Malagoli Rocha

Genes 2017, 8(1), 6; https://doi.org/10.3390/genes8010006 - 23 Dec 2016

Cited by 24 | Viewed by 6724

Abstract

Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways—primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessReview

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

by Gabrielle Bradshaw, Heidi G. Sutherland, Larisa M. Haupt and Lyn R. Griffiths

Genes 2016, 7(12), 130; https://doi.org/10.3390/genes7120130 - 17 Dec 2016

Cited by 17 | Viewed by 5216

Abstract

A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively. In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes. These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies. With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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Open AccessReview

A Review of Computational Methods for Finding Non-Coding RNA Genes

by Qaisar Abbas, Syed Mansoor Raza, Azizuddin Ahmed Biyabani and Muhammad Arfan Jaffar

Genes 2016, 7(12), 113; https://doi.org/10.3390/genes7120113 - 03 Dec 2016

Cited by 18 | Viewed by 6991

Abstract

Finding non-coding RNA (ncRNA) genes has emerged over the past few years as a cutting-edge trend in bioinformatics. There are numerous computational intelligence (CI) challenges in the annotation and interpretation of ncRNAs because it requires a domain-related expert knowledge in CI techniques. Moreover, there are many classes predicted yet not experimentally verified by researchers. Recently, researchers have applied many CI methods to predict the classes of ncRNAs. However, the diverse CI approaches lack a definitive classification framework to take advantage of past studies. A few review papers have attempted to summarize CI approaches, but focused on the particular methodological viewpoints. Accordingly, in this article, we summarize in greater detail than previously available, the CI techniques for finding ncRNAs genes. We differentiate from the existing bodies of research and discuss concisely the technical merits of various techniques. Lastly, we review the limitations of ncRNA gene-finding CI methods with a point-of-view towards the development of new computational tools. Full article

(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)

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