Metabolic Reprogramming of Triple-Negative Breast Cancer: The Role of miRNAs

MicroRNAs (miRNAs) are well known to influence the expression of the genes that regulate critical cellular functions. Various reports have suggested that they play critical roles in breast cancer metabolism through the regulation of various metabolic pathways, including the metabolism of glucose, lipids, glycolysis and the mitochondrial tricarboxylic acid cycle (TCA). miRNAs regulate the metabolic process by targeting key molecules (enzymes, kinases transporters) or by modifying the expression of key transcription molecules. In addition, miRNAs can indirectly regulate mRNA translation by targeting chromatin-remodeling enzymes. Furthermore, miRNAs influence the expression of both oncogenes and tumor suppressors and have a major impact on PI3K/AKT, HIF, and MYC signal transduction, which contributes to the metabolic phenotype in human cancer. Although human epidermal growth factor and endocrine therapies have been effective in treating breast cancer, for locally advanced and distant metastases mortality remains high. Drug resistance and recurrence remain major hurdles for advanced breast cancer therapy. Given the critical influence of metabolic reprogramming in the progression of neoplasm, tumorigenesis and metastasis, research should focus on novel targets of metabolic enzymes to reverse drug resistance and improve overall survival rates. Blocking the miRNAs that contribute to metabolic reprogramming or the use of exogenous miRNAs as antisense oligonucleotides, may be an effective way to treat aggressive, chemo-resistant cancers. This review summarizes current knowledge on the mechanism of action of miRNAs in altering the metabolism of cancer cells and presents possible therapeutic approaches to treating breast cancers that are resistant to current drugs.

Exosomic microRNAs as emerging key regulators of intercellular communication in the tumor microenvironment and beyond

MicroRNAs (miRs) are small non-coding RNAs with key gene regulatory functions. Recent evidence has shown that miRs have a central role in shaping the biology of the Tumor Microenvironment (TME). The discovery that some exosomes contain high levels of miR cargo that shuttle between cells and mediate intercellular cross-talk has shifted the focus of miR research towards understanding the biological role of exosomic miRs. In this review, we highlight the emerging role of exosomic miRs in molding the tumor microenvironment towards pro-tumor conditions by altering intercellular communication. We briefly discuss some mechanisms of selective loading of miRs into exosomes, as well as emerging evidence that exosomic miRs are present in all biological fluids. Furthermore, we describe the differences in the exosomic miR signatures between cancer patients and healthy controls, and the potential role of exosomic miRs as diagnostic, prognostic, and therapeutic biomarkers.

microRNA-based diagnostic and therapeutic opportunities in lung cancer

AbstractmicroRNAs (miRNAs) are a class of non-coding RNA which suppress target gene expression. miRNAs are involved in most physiological and pathological process, including carcinogenesis. miRNA expression profiles help to improve lung cancer diagnosis, classification and prognostic information. Tumor suppressive and oncogenic miRNAs have been discovered and their functions have been investigated. Emphasis is placed on the development of miRNA-based methods for lung cancer diagnosis and therapy and future directions are proposed.

MicroRNAs are central to osteogenesis: a review with a focus on cardiovascular calcification

Cardiovascular calcification, manifested by coronary artery calcification and aortic valve stenosis, is a widespread condition that is becoming more common with the aging of the general population. No disease-modifying therapies currently exist for any forms of cardiovascular calcification. A number of similarities exist between pathological calcification in cardiovascular tissue and physiological calcification in bone, termed osteogenesis. MicroRNAs are small noncoding RNAs that have been shown to have multiple effects throughout the cardiovascular system. In this review, we discuss the pre-clinical evidence supporting a role for microRNAs in osteogenesis, with a focus on cardiovascular calcification. The microRNAs with most evidence implicating them in the disease process are the miR-17~92 cluster, miR-23a/27a/24-2 family, miR-26a, miR-29b, the miR-30 family, miR-31, miR-125b, miR-133a, miR-143/145, miR-155, and miR-221/222. We also highlight the limitations of current evidence in this field, such as the lack of studies using high-throughput technologies.

miRNA function and modulation in stem cells and cancer stem cells

Stem cells belong to a unique class of cells that is collectively responsible for the development and subsequent maintenance of all tissues comprising multicellular organisms. These cells possess unique characteristics that allow them to remain in a pluripotent state, while also continuing to generate differentiated cells. microRNAs, a specialized class of non-coding RNAs, are integral components of the network of pathways that modulates this combination of abilities. This review highlights recent discoveries about the roles miRNAs play in governing stem cell phenotype, and discusses the potential therapeutic utility that miRNAs may have in the treatment of multiple diseases. Additionally, it addresses a novel mode of regulation of stem cell phenotype through lincRNA-mediated modulation of select miRNAs, and the role of secreted, stem cell-derived miRNAs in exerting a paracrine influence on surrounding non-stem cells.

From life to death: microRNAs in the fine tuning of the heart

The heart is one of the most important vital organs, and any malfunctioning of the heart and its blood vessels may contribute to cardiovascular disorders. Diseases of the cardiovascular system represent the most common cause of human morbidity and mortality around the globe. Thus, there is always a need for innovative new therapies and diagnostics for cardiovascular disorders. In the past decades, a plethora of tiny, endogenous, singlestranded RNA sequences called microRNAs (miRNAs) has been studied meticulously in cardiovascular development and pathophysiology, providing a new dimension to the heart’s biology. miRNAs posttranscriptional inhibit the gene expression of specific mRNA targets through Watson– Crick base pairing between the miRNA “seed region” and the 3′ untranslated regions (UTRs) of target mRNAs. Better recognized as “master switches”, miRNAs are emerging as vital regulators of mammalian cardiovascular development and disease and thus are helpful in understanding therapeutic targets and diagnostics for a variety of cardiovascular disorders. In this review, a detailed discussion of the roles of various microRNAs in cardiovascular development and pathophysiology with potential therapeutics is considered.

Circulating MicroRNAs as Biomarkers in Coronary Heart Disease and Heart Failure

MicroRNAs (miRNAs) are small non-coding, single-stranded RNAs (19–25 nucleotides long) that regulate expression of multiple target genes, predominantly by binding to the 3′ untranslated region of messenger RNA (mRNA) transcripts, resulting either in translational inhibition or mRNA degradation. miRNAs are found in many bodily fluids, including plasma and serum, and are protected from degradation in the circulation through association with lipids, proteins, or microparticles, making them attractive disease biomarker candidates. Circulating levels of cardiac miRNAs (including miR-1, miR-133a, miR-208a, miR-208b, and miR-499) have been frequently reported as elevated in both coronary heart disease (CHD) and heart failure (HF) and have been proposed as candidate biomarkers that reflect the severity of myocardial injury. Subsequent large, array-based screening studies comparing patients and controls have identified altered expression of additional miRNAs, not just those of cardiac origin. However, among these studies there has been little consensus as to which miRNAs are top candidates for diagnosis or prognosis in either CHD or HF. The measurement of circulating miRNAs is further complicated by the timing of collection, especially after acute cardiac events while miRNA levels in blood may be rapidly changing; confounding influences from medications or contaminating blood cells at the time of sampling; and the need for standardization of normalization strategies. This review evaluates recent developments in the identification of circulating miRNAs as markers for diagnosis and prognosis in CHD and HF, and the methodological issues in measurement of circulating miRNAs.

Can miRNA Biomarkers Be Utilized to Improve the Evaluation and Management of Pancreatic Cystic Lesions?

This article reviews the current strategies and challenges of diagnosing pancreatic cystic lesions, and presents an overview of molecular tools that are available to enhance diagnostic accuracy. Specifically, we highlight the emergence of microRNAs (miRNAs) as diagnostic markers. miRNA signatures have been reported for both solid tissue and biofluid specimens, including cyst fluid, collected from patients with solid and cystic pancreatic lesions. These miRNA signatures offer the opportunity to improve molecular characterization of pancreatic lesions, to help guide clinical management through early diagnosis and informed prognosis, and to provide novel therapeutic targets for pancreatic cancer.

Diet-Derived MicroRNAs: Separating the Dream from Reality

Background: Both pleiotropic and ubiquitous, microRNAs (miRNAs) exert control over a wide range of cellular functions. They have been detected in virtually every extracellular fluid in the mammalian body, and many circulate substantial anatomical distances in plasma. Thus, secreted miRNAs are valuable not only as diagnostic tools but also may serve as novel biological effectors that can be transmitted between source and recipient tissue.Design: This review will discuss the possibility of delivering functional miRNAs from exogenously derived dietary sources. We will examine prior research interrogating the existence and relevance of such a mechanism.Findings: Recent findings have reported cross-kingdom transfer of specific plant-derived miRNAs to mammalian tissue following consumption of plant-based foods. These exogenous miRNAs were reported to be active in the recipient organisms, directing changes in gene expression at distant organ sites. In spite of this, subsequent studies have been unable to find evidence of substantial exogenous diet-derived miRNAs in mammalian circulation or tissues, regardless of diet.Conclusion: Further examination of diet-derived miRNA uptake is ongoing, but it does not appear that horizontal delivery of miRNAs via normal dietary intake is a generalizable or frequent process to maintain robust expression of these miRNAs in most higher-order animal organisms.

miR-29a and miR-30c negatively regulate DNMT 3a in cardiac ischemic tissues: implications for cardiac remodelling

Recent evidences indicate that epigenetic changes play an important role in the transcriptional reprogramming of gene expression that characterizes cardiac hypertrophy and failure and may dictate response to therapy. Several data demonstrate that microRNAs (miRNAs) play critical roles both in normal cardiac function and under pathological conditions. Here we assessed, in in vivo rat models of myocardial infarction (MI) and ischemia-reperfusion (IR), the relationship between two miRNAs (miR-29a and miR-30c) and de novo methyltransferase (DNMT3a) which, altering the chromatin accessibility for transcription factors, deeply impacts gene expression. We showed that the levels of members of miR-29 and miR- 30 families were down regulated in ischemic tissues whilst the protein levels of DNMT3a were increased, such a relation was not present in healthy tissues. Furthermore, by an in vitro assay, we demonstrated that both miRNAs are able to down regulate DNMT3a by directly interacting with DNMT3a 3’UTR and that miR-29a or miR-30c overexpression in the cardiac HL1 cell line causes decrease of DNMT3a enzyme both at the mRNA and protein levels. Our data, besides confirming the down regulation of the miR-29a and miR-30c in infarcted tissues, envisage a cross-talk between microRNAs and chromatin modifying enzymes suggesting a new mechanism that might generate the alterations of DNA methylation often observed in myocardial pathophysiology.