1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Introduction: Long non-coding RNAs (lncRNAs) are RNA molecules that structurally resemble mRNA but do not encode proteins. Studies have been associated this class of non-coding RNA with the development of several disease, among them the different types of leukemia. However, the results are contradictory. Thus, we performed a systematic review of the literature available in order to better understand the involvement of lncRNAs in the development of leukemia. Materials and Methods: Pubmed and Embase databases were used to identify all studies that evaluated the expression of one or more lncRNA between human samples (peripheral blood, bone marrow) with leukemia (cases) and without leukemia (controls). Results: A total of 3675 articles were found in the databases, and after exclusion of articles that did not meet the eligibility criteria, 86 articles were included in this systematic review. In the 86 included studies, 3927 lncRNAs were differentially expressed between cases and controls. Among these, 110 lncRNAs were reported as being altered in samples from at least 2 studies and only 16 of them in ≥ 3 studies, which were selected for further evaluation. Of these, 12 lncRNAs were consistently dysregulated between cases and controls (CCAT1, CCDC26, CRNDE, HOTAIR, KCNQ5IT1, LINC00265, MALAT1, PVT1, SNHG5,TUG1: increased in cases, MEG3 and NEAT1: decreased in cases) in human samples of patients with some type of leukemia. Conclusion: Our data demonstrate that 12 lncRNAs are dysregulated in leukemia.

Introduction

Leukemia is a type of cancer that affects the blood and bone marrow and is characterized by the uncontrolled production and accumulation of blood cells (1). According to American Cancer Society (2), cancer the second leading cause of deaths among children, adolescents and young adults younger than 20 years, and leukemia is the main type of cancer that affect children. In addition, 381,774 people are living with or in remission from leukemia in the US (2). Radiation exposure, viral infections, ethnicity, gender and genetic mutations are some of the risk factors of leukemia (1). However, more studies are necessary to better understand the development and the pathogenesis of the different types of leukemia. In this context, epigenetic factors, such as non-coding RNAs (ncRNA), have been associated with leukemia development. NcRNAs are a group of regulatory RNAs that are not translated into protein (3). NcRNAs longer than 200 nucleotides are classified as long non-coding RNAs (lncRNAs). LncRNAs are located in nucleus, where they can act as molecular scaffolds, help in alternative splicing or modify chromatin structures. In addition, there are some lncRNAs that have functions in cytoplasm, such as modulating translation, promoting or inhibiting mRNA degradation, and acting as miRNAs sponges (4).

1- Introduction

2- Structural elements of mRNA

3- Improving the stability and translation of mRNA

4- Avoiding immunogenicity of mRNA

5- 5 mRNA delivery

6- Preclinical and clinical advances of mRNA therapeutics

7- Concerns over the mRNA medicinal industry

8- Summary and perspective

References

Abstract

Messenger RNA (mRNA)-based therapeutics hold the potential to cause a major revolution in the pharmaceutical industry because they can be used for precise and individualized therapy, and enable patients to produce therapeutic proteins in their own bodies without struggling with the comprehensive manufacturing issues associated with recombinant proteins. Compared with the current therapeutics, the production of mRNA is much cost-effective, faster and more flexible because it can be easily produced by in vitro transcription, and the process is independent of mRNA sequence. Moreover, mRNA vaccines allow people to develop personalized medications based on sequencing results and/or personalized conditions rapidly. Along with the great potential from bench to bedside, technical obstacles facing mRNA pharmaceuticals are also obvious. The stability, immunogenicity, translation efficiency, and delivery are all pivotal issues need to be addressed. In the recently published research results, these issues are gradually being overcome by state-of-the-art development technologies. In this review, we describe the structural properties and modification technologies of mRNA, summarize the latest advances in developing mRNA delivery systems, review the preclinical and clinical applications, and put forward our views on the prospect and challenges of developing mRNA into a new class of drug.

INTRODUCTION

Messenger RNA (mRNA) has become an attractive subject of basic and applied research since it was first discovered in 1960s (Brenner et al., 1961). Accordingly, the understanding of mRNA has shifted from a simple link between DNA and protein to a versatile molecule that regulates the functions of genes in all living organisms. Based on this change, numerous types of mRNA-based therapeutics have emerged. In 1990, Wolff et al. firstly reported that intramuscular injection of mRNA into the skeletal muscle of mice led to the expression of encoding proteins (Wolff et al., 1990). Since then, mRNA- based therapeutics have been exploited in a variety of applications, including cancer immunotherapy, infectious disease vaccines, protein substitution and cellular genetic engineering. In 2001, ex vivo mRNA transfected dendritic cells entered clinical trial for the first time (Heiser et al., 2002), and hundreds of mRNA-based clinical trials have been launched over the past two decades. However, mRNA was not considered a new class of drug in the first decades after its discovery. Obstacles such as instability and immunogenicity have hampered its development, making it less pursued than DNA in gene therapy (Burnett and Rossi, 2012; Crooke et al., 2018; Geall et al., 2013; Hajj and Whitehead, 2017; Kallen and Thess, 2014; Kreiter et al., 2011; Reautschnig et al., 2017; Sahin et al., 2014; Van et al., 2015). In recent years, these key problems have been mainly solved by introducing modified nucleosides into mRNA sequences and developing various RNA packaging and delivery systems. A lot of evidences not only proved that mRNA can mediate superior transfection efficiency and longer protein expression time, but also revealed the main advantages of mRNA over DNA. The advantages of mRNA include: (1) mRNA does not need to enter the nucleus to be functional.

1- Introduction

2- Noncoding RNAs and sirtuins function in cancer drug resistance

3- Future prospective and conclusion

References

Abstract

Cancer is a rising and major health issue around the world. The acquisition of resistance to chemotherapeutic drugs is a great obstacle for the effective treatment of nearly all cancers. Drug resistance is regulated by multiple factors and mechanisms including genetic mutations, abnormal expression of some cellular transporters such as multidrug resistance (MDR) transporters, changes in apoptotic pathways, cancer stem cells, tumor microenvironment, and noncoding RNAs (ncRNAs). Evidence clearly indicates a key role for sirtuins in several characteristics of cancer drug resistance. Recent studies demonstrated the crucial impact of some ncRNAs on sirtuins expression leading to modulation of chemotherapy resistance in cancers. In this review, we will focus on the current findings about the impacts of ncRNAs on the sirtuins pathway and their role in drug resistance of cancer.

Introduction

Cancer is considered a complex disease associated with some genetic mutations, deletions, epigenetic alterations and chromosomal translocations that are involved in cancer initiation, promotion, metastasis and drug resistance (Bach and Lee, 2018). Chemotherapy is one of the most widely used therapies for the treatment of cancer and improves the lifespan of patients. However, prolonged utilization of chemotherapeutic drugs. may lead to drug resistance which is a major issue in cancer treatment (Szakacs et al., 2006). Based on statistical reports, over than 90% of deaths in patients with different types of cancer are associated with chemotherapeutic drug resistance (Li et al., 2008; Longley and Johnston, 2005). Cancer cells apply many different mechanisms to impede drug treatment, including the genetic mutations, cell cycle alterations, apoptosis induction, drug metabolism, efflux alterations and DNA methylation (Balch et al., 2004; Gillet and Gottesman, 2010; Xia and Hui, 2014). NcRNAs have been reported to play an essential role in determining drug sensitivity or restoring drug sensitivity in resistant cells in many cancers. (Kapranov et al., 2010). NcRNAs are RNA molecules that do not code any protein. However, they exert an important impact on the expression of more than 60% of human genes. They are classified into two main groups including the most studied microRNAs (miRNAs) and the long non-coding RNAs (lncRNA) (Kapranov et al., 2010). MiRNAs are single-stranded RNAs, 19-23bp in length and account for approximately 30% of gene expression regulation. MiRNAs can bind to the 3′ untranslated regions (UTRs) of their target mRNAs and regulate gene expression. The most important function of miRNAs is the suppression of gene expression (Omidkhoda et al., 2019; Szulwach et al., 2010). lncRNAs are transcripts with 200 nt to ~100 kb in length. They do not have any significant open reading frames. lncRNAs are poly-adenylated and located within the cell nucleus or cytosol. They can regulate the expression of genes by cis-acting or trans-acting regulation. Cis-acting lncRNAs affect the expression of neighboring genes by acting at the site of transcription, while trans-acting lncRNAs affect the expression of genes by acting away from the site of synthesis (Barangi et al., 2019; Batista and Chang, 2013).

1- Introduction

2- Materials and methods

3- Results

4- Discussion

5- Conclusion

References

Abstract

Qinchuan cattle is one of the five yellow cattle breeds in China with good performance of meat. The proliferation and differentiation level of muscle and fat are closely related to the growth and development of the organism and are the key factors affecting the quality of meat. In order to study the effect of lncRNA on the fat tissues of Qinchuan cattle, six calf and adult bovine adipose tissues were selected for high-throughput sequencing. We obtained 3,716 lncRNA candidates from calves and adult cattle fat samples, among them 789 lncRNA were annotated and 2,927 lncRNA were novel lncRNA. A number of lncRNAs were highly abundant, and 119 lncRNA were differentially expressed between two developmental stages. We further validated several differentially expressed lncRNAs using qPCR, and the results were consistent with the sequencing data. Therefore, we conclude that lncRNA may play an important role in adipose tissue in different age groups of cattle.

Introduction

Fat is synthesized from glycerin and fatty acids and is an important part of the organism. As the core of the nutritional value of meat, it has a positive effect on the appearance, texture, flavor, hardness and shelf life of the meat1 . However, the excessive deposition of fat not only affects meat quality, but also risks to human health. Therefore, clarifying the regulation mechanism of lipogenesis is of great significance for improving meat quality. Lipogenesis is a complex and elaborate procedural regulation process involving a series of transcription factors2 . At present, more and more researchers have reported on the biological processes of fat synthesis. 3, 4 Numerous studies have shown that the peroxisome proliferator-activated receptor (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) play a key role in this process. However, lipogenesis involves multiple gene expression, signal transduction, and network regulation. The process is complex and new regulatory factors are constantly being identified. Recent studies have shown that long noncoding RNAs (lncRNAs) also have important regulatory effects on adipogenesis, but there are few studies in cattle.

1- Introduction

2- Materials and methods

3- Results

4- Discussion

References

Abstract

Ribonuclease P (RNase P) is an RNA processing enzyme essential for production of functional tRNAs. Bacterial RNase P is a ribozyme, i.e., an RNA-based enzyme, which functions in all bacteria including those growing at high temperatures (≥55 °C). We examined three bacterial RNase P ribozymes, one from a mesophilic bacterium and two from thermophilic bacteria, to understand the factor(s) providing efficient catalytic ability under conditions of high temperature. Thermophilic RNase P ribozymes show structural adaptations to allow correct folding at high temperature. The presence of a molecular crowder significantly enhanced the catalytic efficiency of thermophilic RNase P ribozyme reactions at 55 °C, while it modestly reduced the upper limit of the reaction temperature.

Introduction

Ribonuclease P (RNase P) is a class of RNA processing enzymes, the primary role of which is to remove 50 leader sequences from precursor tRNAs (Fig. 1A) [1]. Bacterial RNase P enzymes are commonly composed of one large RNA (typically ca. 300e400 nucleotides) and one small basic protein (ca. 120 amino acids). Bacterial RNase P is classed as a ribozyme because its catalytic ability originates from its RNA component, which can promote the sitespecific cleavage of pre-tRNAs in vitro without the protein component [1,2]. Bacterial RNase P ribozymes have a modular architecture consisting of two structural domains [1,3,4]: the Cdomain (catalytic domain) containing elements essential for catalysis, and the S-domain (specificity domain) that plays an important role in the specific recognition of pre-tRNA substrates (Fig. 1B) [5,6]. As cleavage of the 50 leader sequence is an essential step in production of functional tRNAs, RNase P ribozymes have to function in all bacterial species growing under various environmental conditions, including various growth temperatures. The RNase P ribozyme is also considered to have emerged at an early stage in the molecular evolution of life and to have functioned in the last universal common ancestor (LUCA) [7], which was proposed to have lived in hydrothermal vents [8]. Bacteria in several phylums, such as Aquificales, Firmicutes, Thermotogae, and DeinococcuseThermus, are known to grow under conditions of high temperature (65 Ce90 C). They also contain RNase P ribozymes [9e12], which need to be active at their growth temperature. The RNA components of these ribozymes may have adaptations for the high temperature growth conditions, and may require the assistance of external factors including their protein components, other intracellular macromolecules that provide molecular crowding conditions, and inorganic/organic cations other than Mg2þ. Thermophilic RNase P ribozymes from thermophilic bacteria are also interesting from the viewpoint of the RNA world hypothesis because it has been proposed that the RNA world may have emerged at hydrothermal vents [13,14].

1- Introduction

2- Common lethal cancers

3- Investigating miRNA profiling in cancers

4- MiR candidates for early phase group detection

5- Conclusion

References

Abstract

Cancer is considered as a challenging lethal agent around the world and its detection at early stages would help prevention of the high mortality. Among the widely used biomarkers in clinical diagnosis of cancer, extracellular non-coding RNAs as ribonucleic acid biomarkers serve as state-of-the-art candidates for molecular diagnosis. In that regard, microRNAs are of great priority mainly because of high variety and stability in body fluids. Accordingly, common miRNAs among most prevalent cancers could help us (pre)diagnose cancer with high accuracy in target samples. In this study, common lethal cancers to humans were investigated in case of miRNA profiles to determine the possible common correlation between miRNA up-regulation or down-regulation (as a ribonucleic acid biomarker) and developing the cancers. It was shown that among the investigated miRNAs, five typical extracellular miRNAs (miR-18a, miR-21, miR-155, miR-221, and miR-375) dysregulation are predominant in most cancer varieties comprising breast, colon, lung, prostate, pancreas, gastric, ovarian, esophagus and liver. This could serve as an appropriate target site for developing point-of-care approaches for cancer detection e.g. designing diagnostic biosensor-based microarrays or kits for both quantification and qualification of the biomarkers. Besides, the miRNA candidates could be efficiently applied to cancer therapeutic approaches.

Introduction

Cancer keeps on being a remarkable cause of worldwide mortality in spite of many years of effort and cost. Deadliest types of cancers to human includes pancreas, liver, lung and bronchus, prostate/breast, colon, rectum and ovary [1–3]. Most of cancers do not induce clinical symptoms until in the later stages when the therapeutic treatment is no longer an option. However, detection of cancer at first stages, regardless of its origin, greatly increases the chance of effective treatments. In spite of much research in cancer biomarkers, only a few are considered for early diagnosis of common cancers. In addition, there is not a general biomarker for population screening in order to detect both asymptomatic cancers and early-staged cancers. Hence, investigating more sensitive and non-invasive biomarkers is still a promising challenge in cancer diagnosis and prognosis [4]. Accessing circulating cancer biomarkers through biological fluids using liquid biopsy seems to propose a promising cost-effective and non-invasive solution. Literally, cf-miRNAs are considered as ideal circulating cancer biomarkers due to their ease of access and quantification, besides integration with other macromolecules e.g. proteins, and high stability in plasma [5, 6]. MiRNAs are endogenous, small (18–24 nt), non-coding (nc) RNA molecules that play important regulatory roles in cell proliferation, apoptosis, metastasis and angiogenesis [7]. Dysregulated miRNA(s) have both oncogenic and tumor-suppressing effects depending on their corresponding targets. The increase or decrease of miRNAs is related to the role of their target genes in cancer progression or regression. MiRNAs are mainly categorized in two groups: 1) OncomiRs that are up-regulated in cancers to target protein-coding transcripts in tumor suppressive pathways, and consequently increase cell proliferation, invasion and metastasis. 2) Tumor-suppressor miRNAs that repress the oncogenic genes and their down-regulation in cancer increases the oncogenic activity [8]. MiRNAs show various expression patterns in tissue and blood of many cancers in comparison with normal samples. Furthermore, miRNA profiles in cancers with various tissue origins are distinct from each other [9].

1- Introduction

2- Targeting the “undruggable” using gene silencing drugs

3- Nanoparticles as a delivery vehicle for siRNA

4- Current state of play of gene silencing nanodrugs in the clinic

5- Gene silencing nanomedicines for the treatment of pancreatic cancer

6- Challenges and opportunities in pancreatic cancer

7- Concluding remarks

References

Abstract

Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promising approach to revolutionize cancer treatment. Small interfering RNA (siRNA) can be designed to inhibit the expression of any gene which is important given the high degree of genetic heterogeneity present in pancreatic tumors. Despite the potential of siRNA therapies, there are hurdles limiting their clinical application such as poor transport across biological barriers, limited cellular uptake, degradation, and rapid clearance. Nanotechnology can address these challenges. In fact, the past few decades have seen the conceptualization, design, pre-clinical testing and recent clinical approval of a RNAi nanodrug to treat disease. In this review, we comment on the current state of play of clinical trials evaluating siRNA nanodrugs and review pre-clinical studies investigating the efficacy of siRNA therapeutics in pancreatic cancer. We assess the physiological barriers unique to pancreatic cancer that need to be considered when designing and testing new nanomedicines for this disease.

Introduction

Pancreatic ductal adenocarcinoma [referred to as pancreatic cancer (PC)] is the fourth leading cause of cancer-related deaths in developed countries with a dismal five-year survival rate of 8% [1]. PC has seen little improvement in patient survival in the past four decades and is projected to be the second leading cause of cancer mortality by 2025 [2]. Unfortunately, PC is often diagnosed at an advanced stage with the development of metastatic spread at diagnosis [3]. Surgical resection improves patient survival, but only 15-20% of patients have surgically resectable tumors and long-term survival after surgery remains poor [3, 4]. Tragically, our best chemotherapy treatments only improve life by an average of 8-16 weeks [4] and there is an urgent need to develop more effective treatments.

Stress granules are condensates of non-translating mRNAs and proteins involved in the stress response and neurodegenerative diseases. Stress granules form in part through intermolecular RNA-RNA interactions, and to better understand how RNA-based condensation occurs, we demonstrate that RNA is effectively recruited to the surfaces of RNA or RNP condensates in vitro. We demonstrate that, through ATP-dependent RNA binding, the DEADbox protein eIF4A reduces RNA condensation in vitro and limits stress granule formation in cells. This defines a function for eIF4A to limit intermolecular RNA-RNA interactions in cells. These results establish an important role for eIF4A, and potentially other DEAD-box proteins, as ATP-dependent RNA chaperones that limit the condensation of RNA, analogous to the function of proteins like HSP70 in combatting protein aggregates.

Introduction

Eukaryotic cells contain ribonucleoprotein (RNP) granules in the nucleus and cytosol, including P-bodies (PBs) and stress granules (SGs) (Anderson and Kedersha, 2006; Banani et al., 2017). SGs are cytosolic condensates composed of non-translating RNPs that are involved in the stress response, neurodegeneration, and viral infection (Protter and Parker, 2016; Ivanov et al., 2019). SGs typically form in response to translation shutoff induced by noxious stimuli such as arsenite, heat shock, and endogenous inflammatory molecules like prostaglandins, which all lead to phosphorylation of eIF2a and the activation of the integrated stress response (Aulas et al., 2017; Tauber and Parker, 2019). SGs can also form independently of eIF2a phosphorylation in response to inhibition of the eIF4F complex or osmotic stress (Aulas et al., 2017). SGs and other RNP condensates are thought to form in part through multimeric RNA binding proteins crosslinking RNPs into larger networks (Banani et al., 2017; Shin and Brangwynne, 2017). Recent evidence suggests that intermolecular RNA-RNA interactions are involved in SG formation. SGs require a substantial pool of non-translating RNA to form (Protter and Parker, 2016). Thus, elevating the non-translating RNA concentration by injecting exogenous RNA induces SGs (Mahadevan et al., 2013). Furthermore, certain RNAs can seed foci in human cell lysates that recruit many SG proteins (Fay et al., 2017). Strikingly, modest concentrations of yeast total RNA readily condense in physiological salt and polyamine conditions, recapitulating the SG transcriptome in a protein-free context (Khong et al., 2017; Van Treeck et al., 2018), arguing that trans RNA-RNA interactions contribute to SG formation. Messenger RNPs (mRNPs) are recruited to SGs in a biphasic manner, first engaging in transient docking interactions with the SG surface, which then transition into stable locking interactions that leave the RNA immobile within the granule (Moon et al., 2019), implying that surface recruitment of RNAs to SGs is a precursor to a more stable RNP assembly.

Head and neck cancer (HNC), which includes epithelial malignancies of the upper aerodigestive tract (oral cavity, oropharynx, pharynx, hypopharynx, larynx, and thyroid), are slowly but consistently increasing, while the overall survival rate remains unsatisfactory. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient’s appearance and self-image, as well as their ability to breathe, speak, and swallow. Patients with HNC require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapeutics. Chemotherapy is an important part of the comprehensive treatment of tumors, especially advanced HNC, but drug resistance is the main cause of poor clinical efficacy. The most important determinant of this phenomenon is still largely unknown. Recent studies have shown that non-coding RNAs have a crucial role in HNC drug resistance. In addition, they can serve as biomarkers in the diagnosis, treatment, and prognosis of HNCs. In this review, we summarize the relationship between non-coding RNAs and drug resistance of HNC, and discuss their potential clinical application in overcoming HNC chemoresistance.

Background

Head and neck cancer (HNC) is a major global health problem. More than 890,000 new cases of HNC and approximately 450,000 HNC-related deaths occur every year [1,2]. The majority of cases are HN squamous cell carcinoma (HNSCC) [3], involving the stratified epithelium of the oral cavity, pharynx, and larynx, with an overall 5-year survival rate of only 40%–50% [3]. Most HNC is closely related to tobacco and alcohol use [1–3]. Patients with HNC might have symptoms including hoarseness, dysphagia, pain, neck mass, and ulcers, which require a multidisciplinary approach involving surgery, radiation therapy, and chemotherapy [4]. Although the treatment is effective for early and locally advanced disease, the prognosis of recurrent and metastatic disease remains poor [5]. Clinically, more than 65% of patients are diagnosed with advanced disease because of the lack of early diagnosis [6]. However, both radiotherapy and surgery reduce patients’ quality of life at this stage [2]. Radiotherapy usually produces obvious side effects, while surgery can significantly affect the normal physiological structure and function of patients [2,7]. Additionally, targeted therapy for HNC has been incorporated into clinical treatment guidelines, but its clinical response and long-term effect are limited, and high costs are associated with this treatment [8]. In recent years, chemical treatment of advanced HNC has been increasingly recognized [9]. In early phase II clinical trials in patients with advanced HNSCC, significant single-agent response rates were up to 30% [5,10].

The majority of the human genome encodes non-coding RNAs (ncRNAs), species of RNA without protein-coding potential but with powerful regulatory functions in disease onset and progression. Functional studies demonstrate that both coding and ncRNAs underlie various mechanisms in heart disease and that molecules targeting RNA species show promising efficacy in preclinical development. Accompanying the exciting developments in basic RNA biology, an equally provocative field has flourished for the design of RNA-based strategies to generate innovative types of therapeutics against these new “druggable” targets, going beyond our current repertoire of small chemistry or biologics. Here, we review the (bio)chemical basis of RNA-based drug design, provide examples that show promise as translatable drug products in preclinical studies, give an insight in the current barriers that hamper straight-forward clinical translation and discuss future directions that may overcome these hurdles to expand the current pharmacotherapy for myocardial disorders.

RNA avenues for heart disease

Heart diseases are a major cause of morbidity and death in Western societies with little recent progress to reduce their high mortality and are now also steeply on the rise in the developing world [1]. The diseases are preceded by ventricular remodelling and changes in left ventricular mass and volume of the myocardium in response to alterations in loading conditions [2,3]. The molecular events that underlie myocardial remodelling still remain poorly understood. Another major hurdle towards improved therapeutics is that currently cardiovascular disease therapy mainly follows a generic ‘one-size-fits-all’ approach, ignoring the inter-individual differences caused by underlying genetic susceptibility, age, gender or stages of disease. This calls for better disease stratification and introduction of medical breakthroughs to address the key biological mechanisms that derail in subsets of patients, an approach that will likely signal the end of the big block-buster treatments for vast numbers of patients, introducing the concept of “Precision Medicine”. With “Precision Medicine” is meant medical decisions, practices, and interventions tailored to the individual patient who will benefit, sparing expenses and side effects for those who will not. Heart diseases are most commonly provoked by the acute and chronic loss of cardiomyocyte function secondary to coronary artery disease, hypertension, diabetes or combinations thereof, which places a volume load or a pressure load, respectively, on the surviving portion of the myocardium. Chronic “load” causes quite generic responses in the myocardium, such as hypertrophy of cardiac myocytes, cardiac dilatation and interstitial fibrosis. These structural cardiac changes are preceded by changes in the “genomics” of the heart: changes in transcript abundance of protein-coding or non-coding genes and the re-expression of genes that are normally only observed in the embryonic heart [4]. These complex forms of heart disease are referred to as “acquired heart diseases” [5]. Acquired forms of heart disease are contrasted by monogenetic forms of heart disease caused by mutations in single genes identified using candidate gene studies or linkage analysis, leading to hereditary, familial dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) [5]. Since cardiovascular disease mechanisms are typically genomic in nature (hereditary cardiovascular diseases comprise a very small subset of the patient population), new developments will likely derive from a better understanding of our genome. The results of the Encyclopedia of DNA Elements (ENCODE) project demonstrate that at least 80% of our genome is functional, has a regulatory role and is transcribed into various classes of non-coding, regulatory RNAs.

Abstract

MicroRNAs (miRNAs) are well‑conserved noncoding RNAs that broadly regulate gene expression through posttranscriptional silencing of coding genes. Dysregulated miRNA expression in prostate and other cancers implicates their role in cancer biology. Moreover, functional studies provide support for the contribution of miRNAs to several key pathways in cancer initiation and progression. Comparative analyses of miRNA gene expression between malignant and nonmalignant prostate tissues, healthy controls and prostate cancer (PCa) patients, as well as less aggressive versus more aggressive disease indicate that miRNAs may be future diagnostic or prognostic biomarkers in tumor tissue, blood, or urine. Further, miRNAs may be future therapeutics or therapeutic targets. In this review, we examine the miRNAs most commonly observed to be de‑regulated in PCa gene expression analyses and review the potential contribution of these miRNAs to important pathways in PCa initiation and progression.

Introduction

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide and it is the fifth leading cause of cancer deaths.1 Historically, PCa has provided important knowledge to the areas of early diagnosis and treatment of cancer, from highly-sensitive PSA screening and the modern radical prostatectomy, to the current recognition of PCa over-diagnosis and over-treatment of indolent disease. PCa was one of the first solid tumors with a targeted treatment for metastatic disease through androgen deprivation therapy (ADT), which has provided important clinical, molecular, and genetic knowledge of pathways that contribute to cancer progression and tumor cell therapeutic resistance. The PCa field is again paving new paths in cancer management through the active surveillance of low-risk disease, as opposed to more radical treatments, and through the development and approval of several novel targeted drugs for metastatic disease and the metastatic microenvironment.2–4 As more is discovered about PCa biology and as PCa management evolves, our knowledge of microRNA (miRNA) biology and expression has grown. Here, we review the recent discoveries of numerous miRNAs reported to be associated with PCa, and we consider the potential contributions of these miRNAs to PCa biology and cancer management.

Parkinson’s disease (PD) is a neurological disorder characterized by the selective degeneration of dopaminergic neurons within the substantia nigra (Poewe et al., 2017). The resulting loss of dopamine signaling from the substantia nigra to the striatum is the primary cause of the distinctive motor symptoms associated with PD, such as rigidity, slowness in movement (bradykinesia), postural instability, and a resting tremor (Fahn, 2003). This damage is associated with the formation of intraneuronal inclusions, Lewy bodies, and Lewy neurites that are composed primarily of α-synuclein (α-syn) (Spillantini et al., 1997). The misfolding of α-syn is a key step in the development of PD pathology: the results from numerous cell culture and animal experiments indicate that oligomeric and/or fibrillar forms of α-syn are cytotoxic (Lee et al., 2014). However, the events that result in α-syn misfolding are not completely understood, even though multiple molecular pathways and cellular mechanisms that have been identified suggest that regulation of cellular homeostasis is crucial (Lopes da Fonseca et al., 2015). The heritability of PD is complex. For a succinct overview of what is currently believed we recommend, from Cell, SnapShot: Genetics of Parkinson’s Disease (Bras et al., 2015). Rare Mendelian-inherited cases of PD contribute about 10% of disease variability, whereas at least 41 common single nucleotide polymorphism (SNP) variants contribute about 30%, with each of the latter imposing low but significant risk (Chang et al., 2017; Nalls et al., 2014; Verstraeten et al., 2015). > 90% of the identified risk SNPs are located in non-coding DNA, making the assignment of potential functionality or causality difficult. We (Coetzee et al., 2016; Pierce and Coetzee, 2017) and others (Lebouvier et al., 2009; Tyson et al., 2016) have reported that diverse tissues are implicated in PD predisposition, but substantia nigra neurons are clearly most directly involved. Most recently, based on a metaanalysis of PD GWAS studies, 71 candidate loci and putative target genes were reported (Chang et al., 2017). The likely functional processes include inflammation, energy metabolism, protein degradation, vesicle trafficking, small-molecule clearing, cellular import, and oxidative stress responses, and it is clear that several of these processes are not intrinsic to the ultimately affected substantia nigra neuronal cells. Therefore, the relevant tissue and cell types in which these processes, when impaired, lead to PD is a crucial question. The unique properties of substantia nigra dopaminergic neurons may contribute to their vulnerability. Each human dopaminergic neuron contains up to one million axon terminals, many at vast distances from the soma, presenting a serious challenge to maintaining cellular homeostasis (Pissadaki and Bolam, 2013). In comparison, neocortical neurons are estimated to have from a few thousand to a few tens-of-thousands of synapses (DeFelipe et al., 2002). Aging also exacerbates this stress, as neurons do not renew themselves through cellular division and toxic products and other damage can accumulate within a cell. Furthermore, the metabolism of dopamine results in reactive oxidative species that add extra stress to the system (Ryan et al., 2013). However, not all non-dividing neurons or highly arborized neurons are subject to neurodegeneration in PD brains, suggesting that a combination of factors may be responsible for pathogenesis.

ncRNA

In light of the recognized importance of protein molecules in mediating biological functions, RNA was considered originally as merely an intermediate molecule for passing the genetic code from DNA to final protein products, as proposed in the central dogma of molecular biology. This notion was later challenged when an enormous number of ncRNAs were discovered and their significance became increasingly clear (Table 1). Recent advances in sequencing technologies have revealed that at least 70% of the human genome is transcribed into RNA while only less than 2% encodes proteins [1,2]. This has resulted in a paradigm shift in our understanding of the potential impact of the noncoding transcriptome (see Glossary) [3]. Some of the ncRNAs are constitutively expressed in all cells and essential for fundamental aspects of cell biology, thus being known as housekeeping ncRNAs. Housekeeping ncRNAs include small-sized transcripts such as tRNA for carrying amino acids, small nuclear RNA (snRNA) for RNA splicing, and small nucleolus RNA (snoRNA) for RNA modification as well as large-sized transcripts, such as rRNA for protein translation. In addition to the housekeeping ncRNAs, another functionally distinct category of ncRNAs whose primary function is to regulate gene expression is referred to as regulatory ncRNAs. Based on an arbitrary length cutoff of 200 nucleotides, regulatory ncRNAs are roughly divided into small ncRNAs and long ncRNAs (lncRNAs). Depending on the size, biogenesis, action, and targets with which they are associated, small ncRNAs can be further classified into several subgroups including miRNAs, endogenous siRNAs (endo-siRNAs), P elementinduced wimpy testis (PIWI)-interacting RNAs (piRNAs), and many others [4]. miRNAs, endo-siRNAs, and piRNAs often employ their sequences in a complementary manner to silence the expression of their target genes. Nevertheless, lncRNAs can act through genomic targeting, regulation in cis (affecting adjacent genes) or trans (affecting distant genes on different chromosomes), epigenetic mechanisms, and antisense interference to up- or downregulate gene expression due to not only primary sequence similarity but also the formation of secondary structures [5]. Unlike the housekeeping ncRNAs, the expression of these small ncRNAs and lncRNAs is highly regulated in different cell types or at different stages during development. Given the lengthy list of novel ncRNA classes and their extensive regulatory roles, for a discussion of a complete repertoire of the ncRNA transcriptome and their functions the reader is directed to other reviews [3,4].