MicroRNAs and long non-coding RNAs in pancreatic cancer: From epigenetics to potential clinical applications

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two relevant classes of non-coding RNAs (ncRNAs) that play a pivotal role in a number of molecular processes through different epigenetic regulatory mechanisms of gene expression. As a matter of fact, the altered expression of these types of RNAs leads to the development and progression of a varied range of multifactorial human diseases. Several recent reports elucidated that miRNA and lncRNAs have been implicated in pancreatic cancer (PC). For instance, dysregulation of such ncRNAs has been found to be associated with chemoresistance, apoptosis, autophagy, cell differentiation, tumor suppression, tumor growth, cancer cell proliferation, migration, and invasion in PC. Moreover, several aberrantly expressed miRNAs and lncRNAs have the potential to be used as biomarkers for accurate PC diagnosis. Additionally, miRNAs and lncRNAs are considered as promising clinical targets for PC. Therefore, in this review, we discuss recent experimental evidence regarding the clinical implications of miRNAs and lncRNAs in the pathophysiology of PC, their future potential, as well as the challenges that have arisen in this field of study in order to drive forward the design of ncRNA-based diagnostics and therapeutics for PC.     

Coding and non-coding nucleotides': The future of stroke gene therapeutics

Stroke is the foremost cause of death ranked after heart disease and cancer. It is the fatal life-threatening event that requires immediate medical admissions to overcome following morbidity and mortality. The therapeutic advances in stroke therapy have been manipulated with diverse paths for last 5 years. Recent research and clinical trials have investigated a variety of anti-stroke agents including anti-coagulants, cerebro-protective agents, antiplatelet therapy, stem-cell therapy, and specified gene therapy. In recent advanced studies, genetic therapies including noncoding RNAs (ncRNAs), long non-coding RNAs (LncRNAs), small interfering RNAs (siRNAs), microRNAs (miRNAs), Piwi interacting RNAs (PiWi RNAs) have shown better potential as targeted future therapeutics with a better outcome than conventional stroke therapeutics. The potential of targeted gene therapy is much more advanced in not only the induction of neuroprotection but also safer non-toxic targeted therapeutics. In the current state of the art review, we have focused on the recent advancements made towards the stroke with RNA modifications and targeted gene therapeutics.     

The interplay between m6A modification and non-coding RNA in cancer stemness modulation: mechanisms,signaling pathways,and clinical implications

Cancer stemness, mainly consisting of chemo-resistance, radio-resistance, tumorigenesis, metastasis, tumor self-renewal, cancer metabolism reprogramming, and tumor immuno-microenvironment remodeling, play crucial roles in the cancer progression process and has become the hotspot of cancer research field in recent years. Nowadays, the exact molecular mechanisms of cancer stemness have not been fully understood. Extensive studies have recently implicated that non-coding RNA (ncRNA) plays vital roles in modulating cancer stemness. Notably, N6-methyladenosine (m6A) modification is of crucial importance for RNAs to exert their biological functions, including RNA splicing, stability, translation, degradation, and export. Emerging evidence has revealed that m6A modification can govern the expressions and functions of ncRNAs, consequently controlling cancer stemness properties. However, the interaction mechanisms between ncRNAs and m6A modification in cancer stemness modulation are rarely investigated. In this review, we elucidate the recent findings on the relationships of m6A modification, ncRNAs, and cancer stemness. We also focus on some key signaling pathways such as Wnt/β-catenin signaling, MAPK signaling, Hippo signaling, and JAK/STAT3 signaling to illustrate the underlying interplay mechanisms between m6A modification and ncRNAs in cancer stemness. In particular, we briefly highlight the clinical potential of ncRNAs and m6A modifiers as promising biomarkers and therapeutic targets for indicating cancer stemness properties and improving the diagnostic precision for a wide variety of cancers.     

Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

Breast cancer (BC) is the most frequently occurring malignancy in women worldwide. Despite the substantial advancement in understanding the molecular mechanisms and management of BC, it remains the leading cause of cancer death in women. One of the main reasons for this obstacle is that we have not been able to find the Achilles heel for the BC as a highly heterogeneous disease. Accumulating evidence has revealed that noncoding RNAs (ncRNAs), play key roles in the development of BC; however, the involving of complex regulatory interactions between the different varieties of ncRNAs in the development of this cancer has been poorly understood. In the recent years, the newly discovered mechanism in the RNA world is “competing endogenous RNA (ceRNA)” which proposes regulatory dialogues between different RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). In the latest BC research, various studies have revealed that dysregulation of several ceRNA networks (ceRNETs) between these ncRNAs has fundamental roles in establishing the hallmarks of BC development. And it is thought that such a discovery could open a new window for a better understanding of the hidden aspects of breast tumors. Besides, it probably can provide new biomarkers and potential efficient therapeutic targets for BC. This review will discuss the existing body of knowledge regarding the key functions of ceRNETs and then highlights the emerging roles of some recently discovered ceRNETs in several hallmarks of BC. Moreover, we propose for the first time the “ceRnome” as a new term in the present article for RNA research.     

Long non‐coding RNAs in non‐small cell lung cancer as biomarkers and therapeutic targets

Lung cancer‐associated mortality is the most common cause of cancer death worldwide. Non‐coding RNAs (ncRNAs), with no protein‐coding ability, have multiple biological roles. Long non‐coding RNAs (lncRNAs) are a recently characterized class of ncRNAs that are over 200 nucleotides in length. Many lncRNAs have the ability of facilitating or inhibiting the development and progression of tumours, including non‐small cell lung cancer (NSCLC). Because of their fundamental roles in regulating gene expression, along with their involvement in the biological mechanisms underlying tumourigenesis, they are a promising class of tissue‐ and/or blood‐based cancer biomarkers. In this review, we highlight the emerging roles of lncRNAs in NSCLC, and discuss their potential clinical applications as diagnostic and prognostic markers and as therapeutic targets.     

Clinical significance of the interaction between non-coding RNAs and the epigenetics machinery

Non-coding RNAs and epigenetics are remarkable mechanisms of cellular control. In this review we underline the processes by which non-coding RNAs (ncRNAs), shown to be involved in various diseases, are capable of modifying and being modified by the epigenetic machinery, emphasizing the clinical importance of this network in cancer. Many ncRNAs have been described that play important roles in the establishment and maintenance of the epigenome. However, only a few studies deeply take into account the role of ncRNAs from a clinicopathological standpoint. The wide range of interactions between the non-coding RNome and the epigenome, and the roles of these networks in the pathogenesis, prognosis and early diagnosis of many diseases, present new challenges and opportunities for future studies regarding therapeutic strategies in oncology.     

Noncoding RNAs in acute kidney injury

Acute kidney injury (AKI), caused by various stimuli including ischemia reperfusion, nephrotoxic insult, and sepsis, is characterized by abrupt decline of kidney function. Till now, the molecular mechanisms for AKI have not been fully explored and the effective therapies are still lacking. Noncoding RNAs (ncRNAs), a group of biomolecules function at RNA level, are involved in a wide range of physiopathological processes including AKI. MicroRNAs (miRNAs) are the most extensively studied ncRNAs in AKI. Evidence indicated that miRNAs are altered significantly in various types of AKI. Gain-and-loss-of-function studies demonstrated that miRNAs, such as miR-24, miR-126, miR-494, and miR-687, may bind to the 3′-untranslated region of their target genes to regulate inflammation, programmed cell death, and cell cycle in the injury and repair stages of AKI, indicating their therapeutic potential in AKI. In contrast, functions of long noncoding RNAs and circular RNAs in AKI are hot topics but still largely unknown. Additionally, ncRNAs packaged in exosome can be detected in circulation and urine, they may serve as specific biomarkers for AKI. This review summarized the alteration and functional role of ncRNAs and their therapeutic potential in AKI.     

Crosstalk between lncRNAs in the apoptotic pathway and therapeutic targets in cancer

The assertion that a significant portion of the mammalian genome has not been translated and that non-coding RNA accounts for over half of polyadenylate RNA have received much attention. In recent years, increasing evidence proposes non-coding RNAs (ncRNAs) as new regulators of various cellular processes, including cancer progression and nerve damage. Apoptosis is a type of programmed cell death critical for homeostasis and tissue development. Cancer cells often have inhibited apoptotic pathways. It has recently been demonstrated that up/down-regulation of various lncRNAs in certain types of tumors shapes cancer cells' response to apoptotic stimuli. This review discusses the most recent studies on lncRNAs and apoptosis in healthy and cancer cells. In addition, the role of lncRNAs as novel targets for cancer therapy is reviewed here. Finally, since it has been shown that lncRNA expression is associated with specific types of cancer, the potential for using lncRNAs as biomarkers is also discussed.     

Application of exosome-derived noncoding RNAs in bone regeneration: Opportunities and challenges

With advances in the fields of regenerative medicine, cell-free therapy has received increased attention. Exosomes have a variety of endogenous properties that provide stability for molecular transport across biological barriers to cells, as a form of cell-to-cell communication that regulates function and phenotype. In addition, exosomes are an important component of paracrine signaling in stem-cell-based therapy and can be used as a stand-alone therapy or as a drug delivery system. The remarkable potential of exosomes has paved the pathway for cell-free treatment in bone regeneration. Exosomes are enriched in distinct noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs and circular RNAs. Different ncRNAs have multiple functions. Altered expression of ncRNA in exosomes is associated with the regenerative potential and development of various diseases, such as femoral head osteonecrosis, myocardial infarction, and cancer. Although there is increasing evidence that exosome-derived ncRNAs (exo-ncRNAs) have the potential for bone regeneration, the detailed mechanisms are not fully understood. Here, we review the biogenesis of exo-ncRNA and the effects of ncRNAs on angiogenesis and osteoblast- and osteoclast-related pathways in different diseases. However, there are still many unsolved problems and challenges in the clinical application of ncRNA; for instance, production, storage, targeted delivery and therapeutic potency assessment. Advancements in exo-ncRNA methods and design will promote the development of therapeutics, revolutionizing the present landscape.     

Genetic regulation by non-coding RNAs

Large scale cDNA sequencing and genome tiling array studies have shown that around 50% of genomic DNA in humans is transcribed, of which 2% is translated into proteins and the remaining 98% is non-coding RNAs (ncRNAs). There is mounting evidence that these ncRNAs play critical roles in regulating DNA structure, RNA expression, protein translation and protein functions through multiple genetic mechanisms, and thus affect normal development of organisms at all levels. Today, we know very little about the regulatory mechanisms and functions of these ncRNAs, which is clearly essential knowledge for understanding the secret of life. To promote this emerging research subject of critical importance, in this paper we review (1) ncRNAs' past and present, (2) regulatory mechanisms and their functions, (3) experimental strategies for identifying novel ncRNAs, (4) experimental strategies for investigating their functions, and (5) methodologies and examples of the application of ncRNAs.     

Genetic regulation by non-coding RNAs

Large scale cDNA sequencing and genome tiling array studies have shown that around 50% of genomic DNA in humans is transcribed, of which 2% is translated into proteins and the remaining 98% is non-coding RNAs (ncRNAs). There is mounting evidence that these ncRNAs play critical roles in regulating DNA structure, RNA expression, protein translation and protein functions through multiple genetic mechanisms, and thus affect normal development of organisms at all levels. Today, we know very little about the regulatory mechanisms and functions of these ncRNAs, which is clearly essential knowledge for understanding the secret of life. To promote this emerging research subject of critical importance, in this paper we review (1) ncRNAs’ past and present, (2) regulatory mechanisms and their functions, (3) experimental strategies for identifying novel ncRNAs, (4) experimental strategies for investigating their functions, and (5) methodologies and examples of the application of ncRNAs.     

Non-coding RNAs regulate tumor cell plasticity

Tumor metastasis is one of the most serious challenges for human cancers as the majority of deaths caused by cancer are associated with metastasis, rather than the primary tumor. Recent studies have demonstrated that tumor cell plasticity plays a critical role in tumor metastasis by giving rise to various cell types which is necessary for tumor to invade adjacent tissues and form distant metastasis. These include differentiation of cancer stem cells (CSCs), or epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET). A growing body of evidence has demonstrated that the biology of tumor cell plasticity is tightly linked to functions of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Therefore, understanding the mechanisms how non-coding RNAs regulate tumor cell plasticity is essential for discovery of new diagnostic markers and therapeutic targets to overcome metastasis.     

Regulatory non‐coding RNAs in acute myocardial infarction

Acute myocardial infarction (AMI) is one of the most common cardiovascular diseases that leads to high mortality and morbidity globally. Various therapeutic targets for AMI have been investigated in recent years, including the non‐coding RNAs (ncRNAs). NcRNAs, a class of RNA molecules that typically do not code proteins, are divided into several subgroups. Among them, microRNAs (miRNAs) are widely studied for their modulation of several pathological aspects of AMI, including cardiomyocyte apoptosis, inflammation, angiogenesis and fibrosis. It has emerged that long ncRNAs (lncRNAs) and circular RNAs (circRNAs) also regulate these processes via interesting mechanisms. However, the regulatory functions of ncRNAs in AMI and their underlying functional mechanisms have not been systematically described. In this review, we summarize the recent findings involving ncRNA actions in AMI and briefly describe the novel mechanisms of these ncRNAs, highlighting their potential application as therapeutic targets in AMI.