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MicroRNAs: Novel Biomarkers for Liver Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (30 June 2015) | Viewed by 88264

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Prof. Dr. Rajagopal N. Aravalli

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Guest Editor

Department of Radiology, University of Minnesota Medical School, MMC 292 Mayo Memorial Building, 420 Delaware Street SE, Minneapolis, MN 55455, USA
Interests: hepatocellular carcinoma; alcoholic liver disease; non-alcoholic steatohepatitis; stem cells and animal models for human liver diseases

Special Issue Information

Dear Colleagues,

During the past decade, it has become clear that microRNAs (miRNAs) play important roles in various liver diseases. MiRNAs are small (~21–23 nucleotides long), non-coding RNAs that regulate post-transcriptional gene expression of their target genes either by inducing translational repression via their binding to partially complementary sequences or by directing mRNA degradation through their binding to perfectly complementary sequences in the 3′ untranslated region (UTR) of messenger RNAs (mRNAs). Each mature miRNA potentially controls many gene targets, and each mRNA is regulated by multiple miRNAs. To date, more than 17,000 distinct mature miRNA sequences have been identified from over 140 species. Because of their functionality in diverse cellular events, miRNA are widely studied in human diseases, as evident from hundreds of clinical trials that are currently underway. Moreover, there is a surge in the filing of patent applications worldwide on the use of miRNAs as therapeutics. Most liver diseases are multifactorial, and, therefore, the expression of a large number of genes, proteins and other molecules from diverse cellular processes and pathways are altered in them. Hence, the use of a combination therapy that targets multiple different steps and pathways, rather than a single test or a set of tests, might be an appropriate strategy to combat liver diseases. MiRNAs are uniquely suited for this purpose as they are capable of targeting many mRNAs simultaneously. In fact, a single miRNA, miR-26a, was recently shown to significantly reduce hepatocellular carcinoma without any toxicity, demonstrating the success of this multi-pronged approach. The articles in this Special Issue of the Journal of Clinical Medicine will provide up-to-date information on the roles of miRNAs in various liver diseases, and on the development of miRNA therapeutics to combat these diseases.

Prof. Dr. Rajagopal N. Aravalli
Guest Editor

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Keywords

miRNA
liver disease
therapy
cirrhosis
hepatocellular carcinoma
cholangiocarcinoma
alcoholic liver disease
non-alcoholic fatty liver disease
non-alcoholic steatohepatitis
hepatitis
hemochromatosis
primary biliary cirrhosis

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Published Papers (11 papers)

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Research

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754 KiB

Open AccessArticle

Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease

by Imeke Goldschmidt, Thomas Thum and Ulrich Baumann

J. Clin. Med. 2016, 5(3), 28; https://doi.org/10.3390/jcm5030028 - 25 Feb 2016

Cited by 17 | Viewed by 5065

Abstract

Circulating microRNAs have been investigated as markers of disease severity in a variety of conditions. We examined whether circulating miR-21 and miR-29a could serve as markers of hepatic fibrosis and disease etiology in children with various liver diseases. Circulating miR-21 and miR-29a were determined in 58 children (21 female, age 0.1–17.8 (median 9.8) years)) with chronic liver disease and compared to histological grading of hepatic fibrosis. 22 healthy children served as controls for circulating miRNAs. Levels of circulating miR-21 appeared to be age-dependent in healthy children. Children with biliary atresia had significantly higher levels of miR-21 compared both to healthy controls and to age-matched children with other cholestatic liver disease. Circulating miR-29a levels in biliary atresia children did not differ from healthy controls, but tended to be higher than in age-matched children with other cholestatic liver disease. Neither miR-21 nor miR-29a correlated well with hepatic fibrosis. Circulating miR-21 and miR-29a levels can potentially serve as non-invasive diagnostic markers to differentiate biliary atresia from other cholestatic disease in infancy. They do not appear suitable as non-invasive markers for the degree of hepatic fibrosis in an unselected cohort of children with various liver diseases. The discriminating effect regarding neonatal cholestasis should be followed up in a prospective longitudinal study. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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618 KiB

Open AccessArticle

Relevance of Rabbit VX2 Tumor Model for Studies on Human Hepatocellular Carcinoma: A MicroRNA-Based Study

by Rajagopal N. Aravalli and Erik N. K. Cressman

J. Clin. Med. 2015, 4(12), 1989-1997; https://doi.org/10.3390/jcm4121954 - 4 Dec 2015

Cited by 15 | Viewed by 5977

Abstract

MicroRNAs are small (~22 nt), noncoding RNA molecules that have critical cellular functions in proliferation, differentiation, angiogenesis and apoptosis. miRNA expression profiling has been used to create signatures of solid tumors and, in many cases, it has been shown to correlate with the severity of the disease. The rabbit VX2 tumor model has been used widely to study a number of human cancers. Our objective in this study is to generate an miRNA signature of the VX2 tumor and to identify miRNAs that are highly expressed in this aggressive tumor. In this study, we performed miRNA profiling of the rabbit VX2 tumor using a microarray that has probes for 1292 unique miRNAs. Their expression in tumor samples was quantified and analyzed. We found that 35 miRNAs were significantly up-regulated in the VX2 tumor. Among these, 13 human miRNAs and eight members of the let-7 family were previously identified in cancers. In addition, we show that the expression of three miRNAs (miR-923, miR-1275, and miR-1308) is novel for the rabbit VX2 tumor, and their expression was not previously shown to be associated with any type of cancer. For the first time, we show the miRNA signature profile for a solid tumor in a rabbit model. miRNAs highly expressed in the VX2 tumor may serve as novel candidates for molecular biomarkers and as potential drug targets. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessArticle

MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer

by Fangmei An, Alexandru V. Olaru, Esteban Mezey, Qing Xie, Ling Li, Klaus B. Piontek and Florin M. Selaru

J. Clin. Med. 2015, 4(9), 1713-1728; https://doi.org/10.3390/jcm4091713 - 26 Aug 2015

Cited by 30 | Viewed by 5339

Abstract

Profound changes in microRNA (miR) expression levels are frequently found in liver cancers compared to the normal liver. In this study, we evaluate the expression of miR-224 in human HCC and CCA, as well as its downstream targets and affected pathways. We show that miR-224 is upregulated in a large cohort of human CCA, similar to its upregulation in human HCC. For the purpose of studying the roles of miR-224 in HCC and CCA, we enforced miR-224 expression in cells. mRNA arrays followed by Ingenuity Pathway Analysis (IPA)-identified putative molecules and pathways downstream of miR-224. Phenotypically, we report that enforced expression of miR-224 increases the growth rate of normal cholangiocytes, CCA cell lines, and HCC cell lines. In addition, we identified, in an unbiased fashion, that one of the major biologic processes affected by miR-224 is Gap1 (G1) to Synthesis (S) transition checkpoint release. We next identified p21, p15, and CCNE1 as downstream targets of miR-224 and confirmed the coordinated downregulation results in the increased phosphorylation of Retinoblastoma (Rb) with resulting G1/S checkpoint release. Our data suggest that miR-224 is a master regulator of cell cycle progression, and that its overexpression results in G1/S checkpoint release followed by accelerated cell growth. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Review

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1906 KiB

Open AccessReview

MicroRNAs in the Evaluation and Potential Treatment of Liver Diseases

by Amar Mahgoub and Clifford J. Steer

J. Clin. Med. 2016, 5(5), 52; https://doi.org/10.3390/jcm5050052 - 10 May 2016

Cited by 21 | Viewed by 7102

Abstract

Acute and chronic liver disease continue to result in significant morbidity and mortality of patients, along with increasing burden on their families, society and the health care system. This in part is due to increased incidence of liver disease associated factors such as metabolic syndrome; improved survival of patients with chronic predisposing conditions such as HIV; as well as advances in the field of transplantation and associated care leading to improved survival. The fact that one disease can result in different manifestations and outcomes highlights the need for improved understanding of not just genetic phenomenon predisposing to a condition, but additionally the role of epigenetic and environmental factors leading to the phenotype of the disease. It is not surprising that providers continue to face daily challenges pertaining to diagnostic accuracy, prognostication of disease severity, progression, and response to therapies. A number of these challenges can be addressed by incorporating a personalized approach of management to the current paradigm of care. Recent advances in the fields of molecular biology and genetics have paved the way to more accurate, individualized and precise approach to caring for liver disease. The study of microRNAs and their role in both healthy and diseased livers is one example of such advances. As these small, non-coding RNAs work on fine-tuning of cellular activities and organ function in a dynamic and precise fashion, they provide us a golden opportunity to advance the field of hepatology. The study of microRNAs in liver disease promises tremendous improvement in hepatology and is likely to lay the foundation towards a personalized approach in liver disease. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessReview

Hepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis

by Mio Kitano and P. Mark Bloomston

J. Clin. Med. 2016, 5(3), 38; https://doi.org/10.3390/jcm5030038 - 16 Mar 2016

Cited by 106 | Viewed by 10822

Abstract

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role in development of hepatic fibrosis and there are intricate regulatory effects of miRNAs on their activation, proliferation, collagen production, migration, and apoptosis. There are multiple differentially expressed miRNAs in activated HSCs, and in this review we aim to summarize current data on miRNAs that participate in the development of hepatic fibrosis. Based on this review, miRNAs may serve as biomarkers for diagnosis of liver disease, as well as markers of disease progression. Most importantly, dysregulated miRNAs may potentially be targeted by novel therapies to treat and reverse progression of hepatic fibrosis. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessReview

Circulating microRNAs as Potential Biomarkers in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma

by Marta B. Afonso, Pedro M. Rodrigues, André L. Simão and Rui E. Castro

J. Clin. Med. 2016, 5(3), 30; https://doi.org/10.3390/jcm5030030 - 3 Mar 2016

Cited by 86 | Viewed by 7979

Abstract

Obesity and metabolic syndrome are growing epidemics worldwide and greatly responsible for many liver diseases, including nonalcoholic fatty liver disease (NAFLD). NAFLD often progresses to cirrhosis, end-stage liver failure and hepatocellular carcinoma (HCC), the most common primary liver cancer and one of the leading causes for cancer-related deaths globally. Currently available tools for the diagnosis of NAFLD staging and progression towards HCC are largely invasive and of limited accuracy. In light of the need for more specific and sensitive noninvasive molecular markers, several studies have assessed the potential of circulating microRNAs (miRNAs) as biomarkers of liver injury and hepatocarcinogenesis. Indeed, extracellular miRNAs are very stable in the blood, can be easily quantitated and are differentially expressed in response to different pathophysiological conditions. Although standardization procedures and larger, independent studies are still necessary, miRNAs constitute promising, clinically-useful biomarkers for the NAFLD-HCC spectrum. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessReview

MicroRNAs in Nonalcoholic Fatty Liver Disease

by György Baffy

J. Clin. Med. 2015, 4(12), 1977-1988; https://doi.org/10.3390/jcm4121953 - 4 Dec 2015

Cited by 72 | Viewed by 15761

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessReview

MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH

by Aida Zarfeshani, Sherry Ngo and Allan M. Sheppard

J. Clin. Med. 2015, 4(11), 1938-1950; https://doi.org/10.3390/jcm4111938 - 16 Nov 2015

Cited by 25 | Viewed by 8256

Abstract

Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern “epidemic” of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver’s limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of “extra-hepatic fat”, a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body’s attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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MicroRNAs in the Cholangiopathies: Pathogenesis, Diagnosis, and Treatment

by Maria Jose Lorenzo Pisarello, Lorena Loarca, Tommy Ivanics, Leslie Morton and Nicholas LaRusso

J. Clin. Med. 2015, 4(9), 1688-1712; https://doi.org/10.3390/jcm4091688 - 26 Aug 2015

Cited by 19 | Viewed by 6911

Abstract

The cholangiopathies are a group of liver diseases resulting from different etiologies but with the cholangiocyte as the primary target. As a group, the cholangiopathies result in significant morbidity and mortality and represent one of the main indications for liver transplant in both children and adults. Contributing to this situation is the absence of a thorough understanding of their pathogenesis and a lack of adequate diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that modify gene expression post-transcriptionally. They have been implicated in the pathogenesis of many diseases, including the cholangiopathies. Thus, in this review we provide an overview of the literature on miRNAs in the cholangiopathies and discuss future research directions. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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Open AccessReview

MicroRNAs: Emerging Novel Clinical Biomarkers for Hepatocellular Carcinomas

by Sumadi Lukman Anwar and Ulrich Lehmann

J. Clin. Med. 2015, 4(8), 1631-1650; https://doi.org/10.3390/jcm4081631 - 18 Aug 2015

Cited by 63 | Viewed by 7214

Abstract

The discovery of small non-coding RNAs known as microRNAs has refined our view of the complexity of gene expression regulation. In hepatocellular carcinoma (HCC), the fifth most frequent cancer and the third leading cause of cancer death worldwide, dysregulation of microRNAs has been implicated in all aspects of hepatocarcinogenesis. In addition, alterations of microRNA expression have also been reported in non-cancerous liver diseases including chronic hepatitis and liver cirrhosis. MicroRNAs have been proposed as clinically useful diagnostic biomarkers to differentiate HCC from different liver pathologies and healthy controls. Unique patterns of microRNA expression have also been implicated as biomarkers for prognosis as well as to predict and monitor therapeutic responses in HCC. Since dysregulation has been detected in various specimens including primary liver cancer tissues, serum, plasma, and urine, microRNAs represent novel non-invasive markers for HCC screening and predicting therapeutic responses. However, despite a significant number of studies, a consensus on which microRNA panels, sample types, and methodologies for microRNA expression analysis have to be used has not yet been established. This review focuses on potential values, benefits, and limitations of microRNAs as new clinical markers for diagnosis, prognosis, prediction, and therapeutic monitoring in HCC. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

by Mitchell R. McGill and Hartmut Jaeschke

J. Clin. Med. 2015, 4(5), 1063-1078; https://doi.org/10.3390/jcm4051063 - 20 May 2015

Cited by 38 | Viewed by 6967

Abstract

Drug-induced liver injury (DILI) is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs) has advanced our knowledge of DILI in two ways: (1) possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified, and (2) circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

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