Development of MicroRNAs as Potential Therapeutics against Cancer

MicroRNAs (miRNAs) are small noncoding RNAs that function at the posttranscriptional level in the cellular regulation process. miRNA expression exerts vital effects on cell growth such as cell proliferation and survival. In cancers, miRNAs have been shown to initiate carcinogenesis, where overexpression of oncogenic miRNAs (oncomiRs) or reduced expression of tumor suppressor miRNAs has been reported. In this review, we discuss the involvement of miRNAs in tumorigenesis, the role of synthetic miRNAs as either mimics or antagomirs to overcome cancer growth, miRNA delivery, and approaches to enhance their therapeutic potentials.

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Coilin enhances phosphorylation and stability of DGCR8 and promotes miRNA biogenesis

Molecular Biology of the Cell ◽

10.1091/mbc.e21-05-0225 ◽

2021 ◽

pp. mbc.E21-05-0225

Author(s):

Katheryn E. Lett ◽

Madelyn K. Logan ◽

Douglas M. McLaurin ◽

Michael D. Hebert

Keyword(s):

Noncoding Rnas ◽

Mature Mirnas ◽

Cajal Body ◽

Mirna Biogenesis ◽

Regulatory Interaction ◽

Small Noncoding Rnas ◽

Control Gene Expression ◽

Processing Steps ◽

Posttranscriptional Level

MicroRNAs (miRNAs) are ∼22 nt small noncoding RNAs that control gene expression at the posttranscriptional level through translational inhibition and destabilization of their target mRNAs. The biogenesis of miRNAs involves a series of processing steps beginning with cropping of the primary miRNA transcript by the Microprocessor complex, which is comprised of Drosha and DGCR8. Here we report a novel regulatory interaction between the Microprocessor components and coilin, the Cajal Body (CB) marker protein. Coilin knockdown causes alterations in the level of primary and mature miRNAs, let-7a and miR-34a, and their miRNA targets, HMGA2 and Notch1, respectively. We also found that coilin knockdown affects the levels of DGCR8 and Drosha in cells with (HeLa) and without (WI-38) CBs. To further explore the role of coilin in miRNA biogenesis, we conducted a series of co-immunoprecipitation experiments using coilin and DGCR8 constructs, which revealed that coilin and DGCR8 can form a complex. Additionally, our results indicate that phosphorylation of DGCR8, which has been shown to increase protein stability, is impacted by coilin knockdown. Collectively, our results implicate coilin as a member of the regulatory network governing miRNA biogenesis.

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Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments

International Journal of Molecular Sciences ◽

10.3390/ijms22115711 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5711

Author(s):

Julian Zacharjasz ◽

Anna M. Mleczko ◽

Paweł Bąkowski ◽

Tomasz Piontek ◽

Kamilla Bąkowska-Żywicka

Keyword(s):

Knee Osteoarthritis ◽

Noncoding Rnas ◽

Pathological Process ◽

Joint Disease ◽

Limited Information ◽

Genetic Changes ◽

Small Noncoding Rnas ◽

Knee Oa ◽

Cartilage Homeostasis

Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world's population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis.

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Mitochondrial microRNAs: A Putative Role in Tissue Regeneration

Biology ◽

10.3390/biology9120486 ◽

2020 ◽

Vol 9 (12) ◽

pp. 486

Author(s):

Sílvia C. Rodrigues ◽

Renato M. S. Cardoso ◽

Filipe V. Duarte

Keyword(s):

Tissue Regeneration ◽

Protein Complexes ◽

Mitochondrial Protein ◽

Noncoding Rnas ◽

Atp Synthesis ◽

Mitochondrial Proteins ◽

Cellular Mechanisms ◽

Small Noncoding Rnas ◽

Mitochondrial Ribosome

The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

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Competing Endogenous RNAs in Hepatocellular Carcinoma—The Pinnacle of Rivalry

Seminars in Liver Disease ◽

10.1055/s-0039-1688442 ◽

2019 ◽

Vol 39 (04) ◽

pp. 463-475 ◽

Cited By ~ 3

Author(s):

Abdelrahman Yousry Afify ◽

Salma Abdulmaqsoud Ibrahim ◽

Mennah Hisham Aldamsisi ◽

Mai Saad Zaghloul ◽

Nada El-Ekiaby ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Noncoding Rnas ◽

Circular Rnas ◽

Solo Performance ◽

Regulatory Pathways ◽

Small Noncoding Rnas ◽

Posttranscriptional Gene Regulation ◽

Competing Endogenous Rnas ◽

Genomic Regulation

AbstractThe role of noncoding transcripts in gene expression is nowadays acknowledged to keep various diseases at bay—despite being referred to as “junk” DNA several years ago. Believed to be at the heart of multiple regulatory pathways, microRNAs (miRNAs) are small noncoding RNAs (ncRNAs) involved in posttranscriptional gene regulation. Recently, the discovery of ncRNAs that compete for shared miRNA pools has dimmed the light on the solo performance of miRNAs in genomic regulation. Indeed, several studies describe RNAs such as long noncoding RNAs, mRNAs, circular RNAs, pseudogenes, and viral RNAs as competing endogenous RNAs (ceRNAs) that sequester miRNAs, allowing for de-repression of downstream miRNA targets. Such integration between coding and noncoding transcripts forms complex ceRNA networks that when dysregulated lead to several diseases such as hepatocellular carcinoma. Here, the authors review perturbed ceRNA networks in hepatocellular carcinoma, describe the role of each in tumorigenesis, and discuss their various clinical implications.

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MicroRNAs and the regulation of aldosterone signaling in the kidney

AJP Cell Physiology ◽

10.1152/ajpcell.00026.2015 ◽

2015 ◽

Vol 308 (7) ◽

pp. C521-C527 ◽

Cited By ~ 8

Author(s):

Michael B. Butterworth

Keyword(s):

Ion Transport ◽

Hormonal Regulation ◽

Noncoding Rnas ◽

Short Review ◽

Biological Molecules ◽

Small Noncoding Rnas ◽

Extracellular Signaling ◽

Corticosteroid Hormones ◽

Mineralocorticoid Hormone

The role of small noncoding RNAs, termed microRNAs (miRs), in development and disease has been recognized for many years. The number of miRs and regulated targets that reinforce a role for miRs in human disease and disease progression is ever-increasing. However, less is known about the involvement of miRs in steady-state, nondisease homeostatic pathways. In the kidney, much of the regulated ion transport is under the control of hormonal signaling. Evidence is emerging that miRs are involved in the hormonal regulation of kidney function and, particularly, in ion transport. In this short review, the production and intra- and extracellular signaling of miRs and the involvement of miRs in kidney disease are discussed. The discussion also focuses on the role of these small biological molecules in the homeostatic control of ion transport in the kidney. MiR regulation of and by corticosteroid hormones, in particular the mineralocorticoid hormone aldosterone, is considered. While information about the role of aldosterone-regulated miRs in the kidney is limited, an increase in the research in this area will undoubtedly highlight the involvement of miRs as central mediators of hormonal signaling in normal physiology.

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Looking for Pyroptosis-Modulating miRNAs as a Therapeutic Target for Improving Myocardium Survival

Mediators of Inflammation ◽

10.1155/2015/254871 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Seahyoung Lee ◽

Eunhyun Choi ◽

Min-Ji Cha ◽

Ki-Chul Hwang

Keyword(s):

Cell Death ◽

Cardiovascular Diseases ◽

Inflammatory Response ◽

Therapeutic Target ◽

Noncoding Rnas ◽

Future Studies ◽

Small Noncoding Rnas ◽

Regulated Cell Death ◽

A Current

Pyroptosis is the most recently identified type of regulated cell death with inflammatory response and has characteristics distinct from those of apoptosis or necrosis. Recently, independent studies have reported that small noncoding RNAs termed microRNAs (miRNAs) are involved in the regulation of pyroptosis. Nevertheless, only a handful of empirical data regarding miRNA-dependent regulation of pyroptosis is currently available. This review is aimed to provide a current update on the role of miRNAs in pyroptosis and to offer suggestions for future studies probing miRNAs as a linker connecting pyroptosis to various cardiovascular diseases (CVDs) and their potential as a therapeutic target for preventing excessive cell death of myocardium during CVDs.

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MicroRNA: Important Player in the Pathobiology of Multiple Myeloma

BioMed Research International ◽

10.1155/2014/521586 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 26

Author(s):

Chonglei Bi ◽

Wee Joo Chng

Keyword(s):

Multiple Myeloma ◽

Drug Response ◽

Molecular Subtypes ◽

Noncoding Rnas ◽

Clinical Staging ◽

Form Complex ◽

Small Noncoding Rnas ◽

Important Player ◽

Novel Biomarkers ◽

Tumor Suppressor Mirnas

Recent studies have revealed a pivotal role played by a class of small, noncoding RNAs, microRNA (miRNA), in multiple myeloma (MM), a plasma cell (PC) malignancy causing significant morbidity and mortality. Deregulated miRNA expression in patient’s PCs and plasma has been associated with tumor progression, molecular subtypes, clinical staging, prognosis, and drug response in MM. A number of important oncogenic and tumor suppressor miRNAs have been discovered to regulate important genes and pathways such as p53 and IL6-JAK-STAT signaling. miRNAs may also form complex regulatory circuitry with genetic and epigenetic machineries, the deregulation of which could lead to malignant transformation and progression. The translational potential of miRNAs in the clinic is being increasingly recognized that they could represent novel biomarkers and therapeutic targets. This review comprehensively summarizes current progress in delineating the roles of miRNAs in MM pathobiology and management.

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MicroRNAs’ Involvement in Osteoarthritis and the Prospects for Treatments

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/236179 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Xiao-Ming Yu ◽

Hao-Ye Meng ◽

Xue-Ling Yuan ◽

Yu Wang ◽

Quan-Yi Guo ◽

...

Keyword(s):

Molecular Mechanisms ◽

Target Genes ◽

Noncoding Rnas ◽

Genetic Changes ◽

Future Studies ◽

Small Noncoding Rnas ◽

Cartilage Homeostasis ◽

Target Binding ◽

And Cartilage

Osteoarthritis (OA) is a chronic disease and its etiology is complex. With increasing OA incidence, more and more people are facing heavy financial and social burdens from the disease. Genetics-related aspects of OA pathogenesis are not well understood. Recent reports have examined the molecular mechanisms and genes related to OA. It has been realized that genetic changes in articular cartilage and bone may contribute to OA’s development. Osteoclasts, osteoblasts, osteocytes, and chondrocytes in joints must express appropriate genes to achieve tissue homeostasis, and errors in this can cause OA. MicroRNAs (miRNAs) are small noncoding RNAs that have been discovered to be overarching regulators of gene expression. Their ability to repress many target genes and their target-binding specificity indicate a complex network of interactions, which is still being defined. Many studies have focused on the role of miRNAs in bone and cartilage and have identified numbers of miRNAs that play important roles in regulating bone and cartilage homeostasis. Those miRNAs may also be involved in the pathology of OA, which is the focus of this review. Future studies on the role of miRNAs in OA will provide important clues leading to a better understanding of the mechanism(s) of OA and, more particularly, to the development of therapeutic targets for OA.

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Small Noncoding RNA CjNC110 Influences Motility, Autoagglutination, AI-2 Localization, Hydrogen Peroxide Sensitivity, and Chicken Colonization in Campylobacter jejuni

Infection and Immunity ◽

10.1128/iai.00245-20 ◽

2020 ◽

Vol 88 (7) ◽

Author(s):

Amanda J. Kreuder ◽

Brandon Ruddell ◽

Kathy Mou ◽

Alan Hassall ◽

Qijing Zhang ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Quorum Sensing ◽

Campylobacter Jejuni ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Wild Type ◽

Content Type ◽

Zoonotic Pathogen ◽

Small Noncoding Rnas

ABSTRACT Small noncoding RNAs (ncRNAs) are involved in many important physiological functions in pathogenic microorganisms. Previous studies have identified the presence of noncoding RNAs in the major zoonotic pathogen Campylobacter jejuni; however, few have been functionally characterized to date. CjNC110 is a conserved ncRNA in C. jejuni, located downstream of the luxS gene, which is responsible for the production of the quorum sensing molecule autoinducer-2 (AI-2). In this study, we utilized strand specific high-throughput RNAseq to identify potential targets or interactive partners of CjNC110 in a sheep abortion clone of C. jejuni. These data were then utilized to focus further phenotypic evaluation of the role of CjNC110 in motility, autoagglutination, quorum sensing, hydrogen peroxide sensitivity, and chicken colonization in C. jejuni. Inactivation of the CjNC110 ncRNA led to a statistically significant decrease in autoagglutination ability as well as increased motility and hydrogen peroxide sensitivity compared to the wild-type. Extracellular AI-2 detection was decreased in ΔCjNC110; however, intracellular AI-2 accumulation was significantly increased, suggesting a key role of CjNC110 in modulating the transport of AI-2. Notably, ΔCjNC110 also showed a decreased ability to colonize chickens. Complementation of CjNC110 restored all phenotypic changes back to wild-type levels. The collective results of the phenotypic and transcriptomic changes observed in our data provide valuable insights into the pathobiology of C. jejuni sheep abortion clone and strongly suggest that CjNC110 plays an important role in the regulation of energy taxis, flagellar glycosylation, cellular communication via quorum sensing, oxidative stress tolerance, and chicken colonization in this important zoonotic pathogen.

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