MicroRNAs in Human Diseases: From Lung, Liver and Kidney Diseases to Infectious Disease, Sickle Cell Disease and Endometrium Disease.

During the menstrual cycle, human endometrium undergoes extensive cyclic, morphologic and biochemical modifications in preparation for embryo implantation that are remarkably consistent during each cycle throughout the reproductive years ( 58 ). This process, which begins with degenerative signals resulting in menstrual bleeding and endometrial shedding, integrates many overlapping and dynamic events to regenerate and become receptive ( 58 ). Pan and Chegini et al. provided evidence showing the endometrial expression of miRNAs and their potential regulatory functions under normal and pathologic conditions such as endometeriosis, dysfunctional uterine bleeding, and endometrial cancer ( 58 ). Recently, a study assessed miRNA expression by microarray analysis in paired ectopic and eutopic endometrial tissues ( 70 ). They identified 14 up-regulated (miR-145, miR-143, miR-99a, miR-99b, miR-126, miR-100, miR-125b, miR-150, miR-125a, miR-223, miR-194, miR-365, miR-29c, and miR-1) and 8 downregulated (miR-200a, miR-141, miR-200b, miR-142-3p, miR-424, miR-34c, miR-20a and miR-196b). In addition, functional analysis suggested that the 673 miRNA targets constitute molecular pathways previously associated with endometriosis, including c-Jun, CREB-binding protein, protein kinase B (Akt), and cyclin D1 (CCND1) signaling ( 70 ). Accordingly, miRNAs are potential therapeutic targets for treating this disease.

Emerging evidence has demonstrated that miRNAs play a major role in a wide range of developmental process including cell proliferation, cell cycle, cell differentiation, metabolism, apoptosis, developmental timing, neuronal cell fate, neuronal gene expression, brain morphogenesis, muscle differentiation and stem cell division. Recent studies provided clear evidence that miRNAs are abundant in the lung, liver and kidney and modulate a diverse spectrum of their functions. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as infectious diseases, sickle cell disease and endometrium diseases as well as lung, liver and kidney diseases. Interestingly, miRNA deficiencies or excess have been correlated with a number of clinically important diseases ranging from infectious diseases to liver diseases. Particularly, accumulating evidence indicates that viruses use their own miRNAs to manipulate both cellular and viral gene expression. Furthermore, viral infection can exert a profound impact on the host cellular miRNA expression profile, and several RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. It is therefore unsurprising that due to their non-immunogenic nature, viral miRNAs represent an elegant tool for the virus to evade the host immune system and likely play a key role in the latent/lytic switch during the viral life cycle. Here I briefly summarized the newly discovered roles of miRNAs in various human diseases including lung, liver and kidney diseases as well as infectious diseases, sickle cell disease and enodmetrium diseases. In the future, distinct miRNA signature involved in diseases should define the role of miRNA in biochemical and immunobiological processes. Furthermore, identification of miRNAs of significance in disease could provide rationale for the design and implementation of disease classification, early detection, disease prognosis and successful therapeutic decision making.

miRNAs are found in almost all species: virus, plants, nematodes, fly, fish, mouse, human, and are implicated in a wide array of cellular and developmental process ( 1 ). There are hundreds of miRNAs encoded in the human genome and thousands of target mRNAs, which illustrates the important regulatory roles of miRNAs in cell development, differentiation, proliferation and apoptosis pathways ( 2 , 3 ). It is not surprising that deregulated miRNAs have been involved in the pathogenesis of many human disease ( 4 - 10 ). miRNAs have recently emerged as important regulators of gene expression. They were formerly thought to mainly repress the translation of target mRNAs, but it has recently been shown that the main function of miRNAs in mammalian system is to decrease target mRNA levels ( 11 ). It is estimated that 20~30 % of all human mRNA are miRNA targets ( 12 ). And so, it is probable that most mRNAs are controlled by miRNAs to some extent. The expression of miRNAs is highly regulated and they are therefore well placed to function as immunomodulators ( 13 ). More recently, miRNA are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of various diseases ( 4 - 7 , 13 , 14 ). Importantly, it has been increasingly reported that miRNAs are associated with disease ( 4 - 6 , 14 - 24 ). However, the pattern among the miRNA-disease association remains largely unclear. In order to dissect the patterns of miRNA-disease associations, a study performed a comprehensive analysis to the human miRNA disease association data, which is manually collected from publication ( 14 ). They built a human miRNA association disease network. Interestingly, miRNAs tend to show similar or different dysfunctional evidence for the similar or different disease clusters, respectively ( 14 ). In addition, they also found that there is a negative correlation between the tissue-specificity of a miRNA and the number of disease it associated and that there is an association between miRNA conservation and disease ( 14 ). Furthermore, they uncovered that miRNAs associated with the same disease tend to emerge as predefined miRNA groups ( 14 ). The effect of inducing or repressing miRNA expression can influence most biological processes, including cell fate specification, cell proliferation, DNA repair, DNA methylation and apoptosis and provide pro-inflammatory or anti-inflammatory stimuli ( 10 , 25 ). Furthermore, with the development of new techniques for genome-wide screening of miRNA expression, abnormal levels of miRNA were identified in various diseases with respect with normal counterpart ( 4 - 6 , 26 , 27 ). All miRNAs are processed and matured through a complex biogenesis process involving multiple protein catalysis accessory proteins, and macromolecular complexes following a coordinated series of event ( 28 - 30 ). They are an abundant class of gene regulatory molecules in multicellular organisms and modulate the expression of many protein-coding genes ( 28 - 30 ). They are transcribed as a huge double-stranded primary transcript (pri-miR) by RNA polymerase II. Subsequently, nuclear enzyme Drosha and Pasha convert this precursor into a double-stranded miRNA precursor of ~70 nulcleotide (pre-miR), which is next transported into the cytoplasm by a mechanisms involving the protein Exportin 5 ( 7 , 13 , 28 , 31 ). Finally, Dicer enzyme processes this precursor into the 22-nucleotide double-stranded miRNA. This duplex is then unwinded, and the leading strand ("guide strand"), one of the two strands, is incorporated into the RNA-induced silencing complex (RISC), which is comprise Agonaute and other proteins ( 7 , 31 , 32 ). miRNAs incorporated in the RISC are able to bind to the 3' untranslated region (UTR) of target mRNAs causing a block of translation or mRNA degradation depending on the level of complementarity ( 28 , 29 ). The other strand so-called "passenger strand" is degraded ( 7 , 28 , 33 ). Very importantly, miRNAS are altered or induced by both environmentally regulated early life developmental factors through epigenetic and miRNA mechanisms, and genetic polymorphisms including protein or miRNA genes ( 34 ). Importantly, miRNA degradation may contribute to several pulmonary disease ( 15 ). In addition, several miRNAs have been shown to be involved in pulmonary allergy and asthma and lung carcinogenesis ( 15 ). There are only few reports focused on the role of miRNAs in chronic obstructive pulmonary disease (COPD), namely miR-146a is involved in COPD ( 16 , 17 , 35 ). Interestingly, changes in miRNA expression are an early event following exposure to cigarette smoke and bronchial airway epithelial cells from current and never smokers differ in the expression of 28 miRNAs in comparison to smokers, whereas the majority of deregulated miRNAs are down regulated in smokers ( 36 ). Very interestingly, it has been reported that many miRNAs may play pivotal role in homeostasis and lung development, and other various pulmonary diseases such as idiopathic pulmonary fibrosis (IPF) ( 15 , 37 - 39 ) and cystic firbrosis ( 40 ). Recent studies provided clear evidence miRNAs are abundant in the liver and modulate a diverse spectrum of liver functions and that deregulation of miRNA expression may be a key pathogenic factor in many liver diseases including viral hepatitis, hepatocellular carcinoma (HCC), and polycystic liver diseases ( 19 ). miR-122 is a liver specific miRNA ( 18 ). Besides miR-122, many other miRNAs are also abundantly expressed in adult liver tissue ( 19 ). Very recently, a large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a 'dirty drug' ( 41 ). It has been known that alcohol-induced gut leakiness is a key factor in alcoholic liver disease (ALD) and it allows endotoxin to enter the circulation and initiate liver damage and that ethanol increases miR-122 expression ( 42 ). It is now clear that key miRNAs are highly expressed in the kidney and can act as effector of TGF-β action and high glucose in diabetic kidney disease ( 20 ). A striking increase in miR-214 was also detected in monocyte from patients with chronic renal failure and that miR-214 specifically binds to phosphatase and tensin homolog (PTEN) mRNA 3'UTR, implicating PTEN as a target gene of miR-214 ( 21 ). Numerous disorders are related to cilia dysfunction, including polycystic kidney disease (PKD), primary ciliary dyskinesia, nephrophthisis ( 43 ) Pandey et al. explored the possibility of miRNA-based regulations in PKD ( 44 ). The authors found that 935 genes were differentially regulated between PKD and healthy controls. As mentioned, many viruses have been founded to encode miRNAs that regulate both viral and host mRNA ( 45 ). It has been shown that miRNAs encoded in the viral genome have the potential to reshape the cellular environment to maximize viral replication ( 24 , 46 ) and viral miRNAs can suppress host cell genes involved in antiviral immunity ( 47 ). Interestingly, some viruses evade immune surveillance by targeting a cellular mRNA with a virally encoded miRNA and viruses use miRNAs not only to regulate their own life cycles but also evade host immune surveillance ( 48 ). In contrast, the cellular miRNAs play an important role in the host, defending against virus infection ( 49 ). As for bacterial infections, tuberculosis remains a major health issue, causing approximately three million deaths every year ( 50 ). Mycobacterium tuberculosis remains one of the most enigmatic bacteria. Currently, Liu et al. performed miRNA expression profiling in peripheral blood mononuclear cells (PBMCs) from pulmonary tuberculosis patients and health controls ( 51 ). They showed that expression of 30 miRNAs was significantly altered during active tuberculosis as compared with healthy controls and 28 miRNAs were up-regulated and 2 miRNAs down-regulated ( 51 ). They also showed that miR-144 * was one of the miRNAs that were over-expressed in active tuberculosis patients. Helocobacter pylori is the main cause of peptic ulceration and gastric adenocarcinoma in human ( 46 , 52 ). H. pylori was able to increase miR-155 expression in gastric epithelial cell lines and gastric mucosal tissue ( 46 ). Currently, a study showed that H. pylori infections alter the expression of oncogenes, tumor suppressor genes and miRNAs ( 52 ). Surprisingly, Salmonella significantly induces several miRNAs and these miRNAs chiefly induced miR-155 and miR-146a, as well as miR-21 ( 53 ). Treatment of immune cells with bacterial lipopolysaccharide (LPS) from Salmonella and Escherichia coli led to the induction of miR-155, miR-132 and miR-146 expression ( 54 ). Since mature erythrocytes are terminally differentiated cells without nuclei and organelles, it is commonly thought that they do not contain nucleic acids ( 55 ). Interestingly, however, human mature erythrocytes contains diverse and abundant miRNAs ( 56 ). Increased expression of these miRNAs in primary erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression ( 57 ). Interestingly, it has been shown that during the menstrual cycle, human endometrium undergoes extensive cyclic, morphologic and biochemical modifications in preparation for embryo implantation and that endometrial expression of miRNAs and their potential regulatory functions are under normal and pathologic conditions such as endometeriosis, dysfunctional uterine bleeding, and endometrial cancer ( 58 ). miRNAs also have an essential role in both the innate and adaptive immune system. Proper miRNA expression is required for correct differentiation of immune cells ( 22 ). Immune responses are symphonies of molecular and cellular interactions, with each player doing its part to produce the composite behavior we see as effective host defense, or when discoordinated, as immunopatholgy or immunodeficiency ( 6 , 59 ). It is therefore not surprising that they have been implicated in various human diseases, including lung diseases ( 15 - 17 , 35 , 60 ), liver diseases ( 18 , 19 , 61 - 63 ), kidney diseases ( 20 , 21 , 43 , 44 , 64 ), infectious diseases ( 22 - 24 , 61 , 65 - 69 ), sickle cell disease ( 55 - 57 ), and endometrium disease ( 58 , 70 ). Here I briefly summarize the newly discovered roles of miRNAs in various human diseases including infectious diseases, sickle cell disease and enodmetrium diseases as well as lung, liver and kidney diseases.