miRNA Function Research Articles

MicroRNAs and colorectal cancer: clinical potential and regulatory networks.

Colorectal cancer (CRC) is a serious global health concern, with a high incidence and mortality rate. Although there have been advancements in the early detection and treatment of CRC, therapy resistance is common. MicroRNAs (miRNAs), a type of small non-coding RNA that regulates gene expression, are key players in the initiation and progression of CRC. Recently, there has been growing attention to the complex interplay of miRNAs in cancer development. miRNAs are powerful RNA molecules that regulate gene expression and have been implicated in various physiological and pathological processes, including carcinogenesis. By identifying current challenges and limitations of treatment strategies and suggesting future research directions, this review aims to contribute to ongoing efforts to enhance CRC diagnosis and treatment. It also provides a comprehensive overview of the role miRNAs play in CRC carcinogenesis and explores the potential of miRNA-based therapies as a treatment option. Importantly, this review highlights the exciting potential of targeted modulation of miRNA function as a therapeutic approach for CRC.

Novel polymorphism rs12402181 in the mature sequence of hsa-miR-3117-3p has a protective effect against breast cancer development by affecting miRNA processing and function.

The online version contains supplementary material available at 10.1007/s13205-023-03765-y.

Post-transcriptional gene silencing in a dynamic RNP world.

MicroRNA (miRNA)-guided gene silencing is a key regulatory process in various organisms and linked to many human diseases. MiRNAs are processed from precursor molecules and associate with Argonaute proteins to repress the expression of complementary target mRNAs. Excellent work by numerous labs has contributed to a detailed understanding of the mechanisms of miRNA function. However, miRNA effects have mostly been analyzed and viewed as isolated events and their natural environment as part of complex RNA-protein particles (RNPs) is often neglected. RNA binding proteins (RBPs) regulate key enzymes of the miRNA processing machinery and furthermore RBPs or readers of RNA modifications may modulate miRNA activity on mRNAs. Such proteins may function similarly to miRNAs and add their own contributions to the overall expression level of a particular gene. Therefore, post-transcriptional gene regulation might be more the sum of individual regulatory events and should be viewed as part of a dynamic and complex RNP world.

Detection of transcriptome-wide microRNA–target interactions in single cells with agoTRIBE

MicroRNAs (miRNAs) exert their gene regulatory effects on numerous biological processes based on their selection of target transcripts. Current experimental methods available to identify miRNA targets are laborious and require millions of cells. Here we have overcome these limitations by fusing the miRNA effector protein Argonaute2 to the RNA editing domain of ADAR2, allowing the detection of miRNA targets transcriptome-wide in single cells. miRNAs guide the fusion protein to their natural target transcripts, causing them to undergo A>I editing, which can be detected by sensitive single-cell RNA sequencing. We show that agoTRIBE identifies functional miRNA targets, which are supported by evolutionary sequence conservation. In one application of the method we study microRNA interactions in single cells and identify substantial differential targeting across the cell cycle. AgoTRIBE also provides transcriptome-wide measurements of RNA abundance and allows the deconvolution of miRNA targeting in complex tissues at the single-cell level.

Advances in the Study of the Transcriptional Regulation Mechanism of Plant miRNAs.

MicroRNAs (miRNA) are a class of endogenous, non-coding, small RNAs with about 22 nucleotides (nt), that are widespread in plants and are involved in various biological processes, such as development, flowering phase transition, hormone signal transduction, and stress response. The transcriptional regulation of miRNAs is an important process of miRNA gene regulation, and it is essential for miRNA biosynthesis and function. Like mRNAs, miRNAs are transcribed by RNA polymerase II, and these transcription processes are regulated by various transcription factors and other proteins. Consequently, the upstream genes regulating miRNA transcription, their specific expression, and the regulating mechanism were reviewed to provide more information for further research on the miRNA regulatory mechanism and help to further understand the regulatory networks of plant miRNAs.

The Roles of MicroRNAs in Obesity: Emphasizing Links with Chronic Kidney Disease and Cardiovascular Disorders

Obesity has become a global epidemic, contributing to the development of numerous chronic diseases, including diabetes, chronic kidney disease (CKD) and cardiovascular disorders. MicroRNAs (miRNAs) have emerged as key regulators in various biological processes, including metabolism, inflammation, and tissue remodeling, making them pivotal players in obesity-related pathologies. This review aims to provide comprehensive insights into the roles of miRNAs in obesity, with a particular emphasis on their involvement in the pathogenesis of CKD and cardiovascular disorders. We highlight the involvement of specific miRNAs in adipose tissue development, energy homeostasis, inflammation, and insulin resistance, contributing to the pathogenesis of obesity. Moreover, we explore the impact of miRNAs on renal fibrosis and inflammation, giving clues on their roles in the development and progression of CKD. Additionally, we discuss the influence of miRNAs on endothelial dysfunction, atherosclerosis, and cardiac remodeling, emphasizing their contribution to obesity-related cardiovascular disorders. Understanding the regulatory functions of miRNAs in these interconnected conditions holds promise for improved diagnosis, prognosis, and therapeutic interventions. Indeed, miRNAs are potential diagnostic biomarkers for obesity-related diseases, although challenges remain to be elucidated before their clinical translation. Furthermore, we highlight the emerging strategies that target miRNAs as therapeutic interventions to mitigate the detrimental effects of obesity on kidney and cardiovascular health.

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

IntroductionOvarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. Materials and methodsADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. ResultsADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. ConclusionADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

DEJKMDR: miRNA-disease association prediction method based on graph convolutional network.

Numerous studies have shown that miRNAs play a crucial role in the investigation of complex human diseases. Identifying the connection between miRNAs and diseases is crucial for advancing the treatment of complex diseases. However, traditional methods are frequently constrained by the small sample size and high cost, so computational simulations are urgently required to rapidly and accurately forecast the potential correlation between miRNA and disease. In this paper, the DEJKMDR, a graph convolutional network (GCN)-based miRNA-disease association prediction model is proposed. The novelty of this model lies in the fact that DEJKMDR integrates biomolecular information on miRNA and illness, including functional miRNA similarity, disease semantic similarity, and miRNA and disease similarity, according to their Gaussian interaction attribute. In order to minimize overfitting, some edges are randomly destroyed during the training phase after DropEdge has been used to regularize the edges. JK-Net, meanwhile, is employed to combine various domain scopes through the adaptive learning of nodes in various placements. The experimental results demonstrate that this strategy has superior accuracy and dependability than previous algorithms in terms of predicting an unknown miRNA-disease relationship. In a 10-fold cross-validation, the average AUC of DEJKMDR is determined to be 0.9772.

Comparison of miRNA transcriptome of exosomes in three categories of somatic cells with derived iPSCs

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) through epigenetic manipulation. While the essential role of miRNA in reprogramming and maintaining pluripotency is well studied, little is known about the functions of miRNA from exosomes in this context. To fill this research gap,we comprehensively obtained the 17 sets of cellular mRNA transcriptomic data with 3.93 × 1010 bp raw reads and 18 sets of exosomal miRNA transcriptomic data with 2.83 × 107 bp raw reads from three categories of human somatic cells: peripheral blood mononuclear cells (PBMCs), skin fibroblasts(SFs) and urine cells (UCs), along with their derived iPSCs. Additionally, differentially expressed molecules of each category were identified and used to perform gene set enrichment analysis. Our study provides sets of comparative transcriptomic data of cellular mRNA and exosomal miRNA from three categories of human tissue with three individual biological controls in studies of iPSCs generation, which will contribute to a better understanding of donor cell variation in functional epigenetic regulation and differentiation bias in iPSCs.

MicroRNAs and their regulators: Potential therapeutic targets in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by pulmonary arterial remodeling. Despite that current combination therapy has shown improvement in morbidity and mortality, a better deciphering of the underlying pathological mechanisms and novel therapeutic targets is urgently needed to combat PAH. MicroRNA, the critical element in post-transcription mechanisms, mediates cellular functions mainly by tuning downstream target gene expression. Meanwhile, upstream regulators can regulate miRNAs in synthesis, transcription, and function. In vivo and in vitro studies have suggested that miRNAs and their regulators are involved in PAH. However, the miRNA-related regulatory mechanisms governing pulmonary vascular remodeling and right ventricular dysfunction remain elusive. Hence, this review summarized the controversial roles of miRNAs in PAH pathogenesis, focused on different miRNA-upstream regulators, including transcription factors, regulatory networks, and environmental stimuli, and finally proposed the prospects and challenges for the therapeutic application of miRNAs and their regulators in PAH treatment.

P07.11.B A NOVEL CRISPR/CAS9 KNOCKOUT LIBRARY UNCOVERS PAN-ESSENTIAL MIRNAS IN HUMAN CANCER CELL LINES

Abstract BACKGROUND MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play an important role during cancer initiation and progression. Genome-wide functional screening using the CRISPR/Cas9 system is a powerful tool to uncover genetic dependencies for distinct tumor entities, and has revealed novel insights into pan-cancer fitness genes. Current libraries are focused on single guide RNAs (sgRNAs) targeting protein-coding genes, thereby limiting functional genomics-based investigations of miRNA function. MATERIAL AND METHODS We here designed a novel CRISPR/Cas9 knockout library of 8,107 distinct sgRNAs targeting a total of 1,769 human miRNAs. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Screen hits per cell line were scored on the basis of a combination of a supervised Bayesian gene essentiality analysis (BAGEL2) and an unsupervised gene ranking algorithm (MAGeCK). miRNA genes that scored across all cell lines, i.e. potentially pan-essential miRNAs, were identified using a combination of the Adaptive Daisy Model (ADaM) algorithm and the Fitness Percentile (FiPer) method. RESULTS In silico analyses revealed that our library has significantly lower off-target activity for protein-coding genes as compared to previously described miRNA-targeting sgRNA libraries, while providing a higher coverage of miRNAs present in the human genome. In total, only 13% (n=230) of all targeted miRNAs induced a fitness effect on one or more cell lines, and the majority (83%) of these genes induced a dependency in less than 50% of the tested cell lines. Pan-cancer fitness gene detection by ADaM or FiPer differed solely on the level of stringency. As such, ADaM and FiPer identified 34 core fitness or 54 common essential miRNAs, respectively, and almost all core fitness genes (97%) were identified as common essential. Preliminary network analyses revealed that protein-coding genes that are regulated by core fitness miRNAs are significantly enriched for cell cycle and p53 signaling networks, providing a first rationale for their dependency profiles in human cancer cell lines. CONCLUSION We here established a novel method for functional investigation of miRNAs by means of genome-wide CRISPR/Cas9 knockout screens. Our sgRNA library outperforms previously established libraries in terms of specificity and overall miRNA coverage, making it a novel tool to investigate miRNA function in a genome-wide fashion. We here use this library to define a first-of-its-kind genome-wide functional annotation of miRNAs, revealing a subset of pan-cancer fitness miRNAs that might regulate essential cellular processes such as cell cycle progression. Our data highlight the wide potential of this library in investigating miRNA function in diverse biological settings.

Retro-miRs: novel and functional miRNAs originating from mRNA retrotransposition

BackgroundReverse-transcribed gene copies (retrocopies) have emerged as major sources of evolutionary novelty. MicroRNAs (miRNAs) are small and highly conserved RNA molecules that serve as key post-transcriptional regulators of gene expression. The origin and subsequent evolution of miRNAs have been addressed but not fully elucidated.ResultsIn this study, we performed a comprehensive investigation of miRNA origination through retroduplicated mRNA sequences (retro-miRs). We identified 17 retro-miRs that emerged from the mRNA retrocopies. Four of these retro-miRs had de novo origins within retrocopied sequences, while 13 retro-miRNAs were located within exon regions and duplicated along with their host mRNAs. We found that retro-miRs were primate-specific, including five retro-miRs conserved among all primates and two human-specific retro-miRs. All retro-miRs were expressed, with predicted and experimentally validated target genes except miR-10527. Notably, the target genes of retro-miRs are involved in key biological processes such as metabolic processes, cell signaling, and regulation of neurotransmitters in the central nervous system. Additionally, we found that these retro-miRs play a potential oncogenic role in cancer by targeting key cancer genes and are overexpressed in several cancer types, including liver hepatocellular carcinoma and stomach adenocarcinoma.ConclusionsOur findings demonstrated that mRNA retrotransposition is a key mechanism for the generation of novel miRNAs (retro-miRs) in primates. These retro-miRs are expressed, conserved, have target genes with important cellular functions, and play important roles in cancer.

Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle-mediated inhibition of cellular cholesterol efflux

While it is recognized that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD), how NAFLD affects the development and progression of CVD remains unclear and debatable. Hence, we aimed to determine the role of steatotic hepatocyte-derived small extracellular vesicles (sEVs) in foam cell formation and atherosclerosis progression. sEVs from steatotic hepatocytes were isolated and characterized. MicroRNA (miRNA) deep sequencing was utilized to identify functional miRNA in sEVs. Lastly, we conducted a cross-sectional study on patients with NAFLD to validate these findings. Treatment of sEVs from steatotic hepatocytes promoted macrophage-derived foam cell formation and atherosclerosis progression via inhibition of ABCA1-mediated cholesterol efflux. Macrophage-specific deletion of Abca1 in ApoE-/- mice abolished the role of steatotic hepatocyte-derived sEVs in atherosclerosis progression. In addition, hepatocyte-specific deletion of Rab27a, which is the key GTPase regulating sEV release, significantly ameliorated high-fat, high-cholesterol diet-induced atherosclerosis progression in ApoE-/- mice. The miRNA deep sequencing results showed that miR-30a-3p was enriched in sEVs from steatotic hepatocytes. miR-30a-3p directly targeted the 3' untranslated region of ABCA1 to inhibit ABCA1 expression and cholesterol efflux. Treatment with antagomiR-30a-3p significantly attenuated atherosclerosis progression in high-fat, high-cholesterol diet-fed ApoE-/- mice. Moreover, serum sEVs from patients with NAFLD and sEV-miR-30a-3p expression were associated with decreased cholesterol efflux levels in foam cells. Steatotic hepatocyte-derived sEVs promote foam cell formation and facilitate atherogenesis via the miR-30a-3p/ABCA1 axis. Reducing sEV secretion by steatotic hepatocytes or targeting miR-30a-3p may be potential therapeutic approaches to slow the progression of NAFLD-driven atherosclerosis. The presence of hepatic steatosis is strongly correlated with the risk of cardiovascular disease and cardiovascular events, yet the molecular mechanisms linking steatosis to progression of atherosclerosis are unclear. Herein, we identified small extracellular vesicles from steatotic hepatocytes as a trigger that accelerated the progression of atherosclerosis. Steatotic hepatocyte-derived small extracellular vesicles promoted foam cell formation via the miR-30a-3p/ABCA1 axis. Our findings not only provide mechanistic insight into non-alcoholic fatty liver disease-driven atherosclerosis but also provide potential therapeutic targets for patients with atherosclerosis.

MiRNA/epithelial-mesenchymal axis (EMT) axis as a key player in cancer progression and metastasis: A focus on gastric and bladder cancers

The metastasis a major hallmark of tumors that its significant is not only related to the basic research, but clinical investigations have revealed that majority of cancer deaths are due to the metastasis. The metastasis of tumor cells is significantly increased due to EMT mechanism and therefore, inhibition of EMT can reduce biological behaviors of tumor cells and improve the survival rate of patients. One of the gaps related to cancer metastasis is lack of specific focus on the EMT regulation in certain types of tumor cells. The gastric and bladder cancers are considered as two main reasons of death among patients in clinical level. Herein, the role of EMT in regulation of their progression is evaluated with a focus on the function of miRNAs. The inhibition/induction of EMT in these cancers and their ability in modulation of EMT-related factors including ZEB1/2 proteins, TGF-β, Snail and cadherin proteins are discussed. Moreover, lncRNAs and circRNAs in crosstalk of miRNA/EMT regulation in these tumors are discussed and final impact on cancer metastasis and response of tumor cells to the chemotherapy is evaluated. Moreover, the impact of miRNAs transferred by exosomes in regulation of EMT in these cancers are discussed.

MicroRNA sequencing analysis reveals injury-induced immune responses of Scylla paramamosain against cheliped autotomy

During pond culture or intensive culture system of crabs (mainly Eriocheir sinensis, Portunus trituberculatus and Scylla paramamosain), high-density farming has typically contributed to a higher limb autotomy level in juvenile animals, especially in S. paramamosain which has a high level of cannibalism. Due to the high limb autotomy level, the survival and growth rates in S. paramamosain farming are restricted, which limit the growth of the mud crab farming industry. MicroRNAs (miRNAs) are small noncoding RNAs that regulate a series of biological processes including innate immune responses by post-transcriptional suppression of their target genes. MiRNAs are believed to be crucial for innate immune process of host wound healing. Many miRNAs have been verified to be required in host immune responses to repair wound and to defense pathogen after tissue damage. However, to our best knowledge, the miRNAs functions of crustacean innate immune reactions against injury induced by limb autotomy have not been studied yet. Here in this study, for the first time, miRNAs involved in the S. paramamosain immune reactions against injury induced by cheliped autotomy were obtained by high-throughput sequencing. A total of 575 miRNAs (518 known miRNAs and 57 novel predicted miRNAs) were obtained, of which 141 differentially expressed microRNAs (93 up-regulated microRNAs and 48 down-regulated microRNAs) were revealed to be modified against cheliped autotomy, and the qPCR results of randomly selected miRNAs confirmed the expression patterns in the miRNAs sequencing data. Numerous immune-related target genes associated with innate immune system were mediated by miRNAs to induce host humoral immune and cellular immune defense to minimize acute physical damage. Furthermore, the genes expression in hemolymph coagulation and melanization pathways, as well as Toll and Imd signaling pathways were mediated by miRNAs to activate host immune responses including melanization and antimicrobial peptides for rapid wound healing and killing invaded pathogens. These results will help to understand injury-induced immune responses in crabs and to develop an effective control strategy of autotomy rate in crabs farming.

MicroRNA-375 Is Induced during Astrocyte-to-Neuron Reprogramming and Promotes Survival of Reprogrammed Neurons when Overexpressed.

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs' expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming.

A survey of computational methods and databases for lncRNA-miRNA interaction prediction.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are two prevalent non-coding RNAs in current research. They play critical regulatory roles in the life processes of animals and plants. Studies have shown that lncRNAs can interact with miRNAs to participate in post-transcriptional regulatory processes, mainly involved in regulating cancer development, metastatic progression, and drug resistance. Additionally, these interactions have significant effects on plant growth, development, and responses to biotic and abiotic stresses. Deciphering the potential relationships between lncRNAs and miRNAs may provide new insights into our understanding of the biological functions of lncRNAs and miRNAs, and the pathogenesis of complex diseases. In contrast, gathering information on lncRNA-miRNA interactions (LMIs) through biological experiments is expensive and time-consuming. With the accumulation of multi-omics data, computational models are extremely attractive in systematically exploring potential LMIs. To the best of our knowledge, this is the first comprehensive review of computational methods for identifying LMIs. Specifically, we first summarized the available public databases for predicting animal and plant LMIs. Secondly, we comprehensively reviewed the computational methods for predicting LMIs and classified them into two categories, including network-based methods and sequence-based methods. Thirdly, we analyzed the standard evaluation methods and metrics used in LMI prediction. Finally, we pointed out some problems in the current study and discuss future research directions. Relevant databases and the latest advances in LMI prediction are summarized in a GitHub repository https://github.com/sheng-n/lncRNA-miRNA-interaction-methods , and we'll keep it updated.

Advances and Trends in miRNA Analysis Using DNAzyme-Based Biosensors.

miRNAs are endogenous small, non-coding RNA molecules that function in post-transcriptional regulation of gene expression. Because miRNA plays a pivotal role in maintaining the intracellular environment, and abnormal expression has been found in many cancer diseases, detection of miRNA as a biomarker is important for early diagnosis of disease and study of miRNA function. However, because miRNA is present in extremely low concentrations in cells and many types of miRNAs with similar sequences are mixed, traditional gene detection methods are not suitable for miRNA detection. Therefore, in order to overcome this limitation, a signal amplification process is essential for high sensitivity. In particular, enzyme-free signal amplification systems such as DNAzyme systems have been developed for miRNA analysis with high specificity. DNAzymes have the advantage of being more stable in the physiological environment than enzymes, easy to chemically synthesize, and biocompatible. In this review, we summarize and introduce the methods using DNAzyme-based biosensors, especially with regard to various signal amplification methods for high sensitivity and strategies for improving detection specificity. We also discuss the current challenges and trends of these DNAzyme-based biosensors.

Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer-Advances and Challenges.

There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.

MiRNAs Epigenetic Tuning of Wall Remodeling in the Early Phase after Myocardial Infarction: A Novel Epidrug Approach.

Myocardial infarction (MI) is one of the leading causes of death in Western countries. An early diagnosis decreases subsequent severe complications such as wall remodeling or heart failure and improves treatments and interventions. Novel therapeutic targets have been recognized and, together with the development of direct and indirect epidrugs, the role of non-coding RNAs (ncRNAs) yields great expectancy. ncRNAs are a group of RNAs not translated into a product and, among them, microRNAs (miRNAs) are the most investigated subgroup since they are involved in several pathological processes related to MI and post-MI phases such as inflammation, apoptosis, angiogenesis, and fibrosis. These processes and pathways are finely tuned by miRNAs via complex mechanisms. We are at the beginning of the investigation and the main paths are still underexplored. In this review, we provide a comprehensive discussion of the recent findings on epigenetic changes involved in the first phases after MI as well as on the role of the several miRNAs. We focused on miRNAs function and on their relationship with key molecules and cells involved in healing processes after an ischemic accident, while also giving insight into the discrepancy between males and females in the prognosis of cardiovascular diseases.