MicroRNAs and liver disease

doi:10.1016/j.trsl.2011.01.008

Translational Research

Volume 157, Issue 4, April 2011, Pages 241-252

https://doi.org/10.1016/j.trsl.2011.01.008 Get rights and content

Posttranscriptional regulation of gene expression is now recognized as an important contributor to disease pathogenesis, whose mechanisms include alterations in the function of stability and translational elements within both coding and noncoding regions of messenger RNA. A major component in this regulatory paradigm is the binding both to RNA stability as well as to translational control elements by microRNAs (miRNAs). miRNAs are noncoding endogenously transcribed RNAs that undergo a well-characterized series of processing steps that generate short single-stranded (∼20–22) RNA fragments that bind to complementary regions within a range of targets and in turn lead to mRNA degradation or attenuated translation as a result of trafficking to processing bodies. This article will highlight selected advances in the role of miRNAs in liver disease including nonalcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma and will briefly discuss the utility of miRNAs as biomarkers of liver injury and neoplasia.

Section snippets

miRNA Biogenesis

miRNAs are transcribed in mono or polycistronic form as single-stranded RNA transcripts from genomic, viral, or plasmid DNA. The resultant transcript, termed pri-miRNA (genomically encoded) or shRNA (viral or plasmid encoded), is cleaved in the nucleus by the RNase Drosha to a 60–90 bp hairpin configuration pre-miRNA. The pre-miRNA is exported from the nucleus via a GTP-dependent Ran/Exportin 5 complex. In the cytoplasm, the pre-miRNA undergoes continued processing by the Dicer complex to a

miRNA Analysis and Bioinformatics

Although the first evidence for miRNA function was observed in 1993,⁷ increased understanding of the importance of miRNAs in physiology has occurred in the last 10 years. To date, more than 17,000 miRNAs have been described in 142 species, with ∼1000 described in humans (miRBase release 16⁸). Because each miRNA can regulate hundreds of target mRNA transcripts, developments in microarray and bioinformatics have been central to understanding miRNA function. A common approach to investigate the

Hepatic miRNAs as Metabolic Modulators and Their Importance in NAFLD

miRNAs have been implicated in regulating key hepatic metabolic functions,³ and over the last few years, some relevant pathways have been selectively interrogated. Initial studies in mice used a loss-of-function approach with either specific antagomirs¹¹ or used antisense oligonucleotide (ASO)-mediated knockdown of miR-122,¹² an abundant miRNA in adult liver.¹³ Either targeting strategy effectively decreased hepatic miR-122 expression in mice, leading to decreased serum cholesterol levels

miRNAs and Hepatitis C Virus (HCV)

Experience with RNAi in plants and invertebrates would argue for a conserved role for miRNA in the innate response to viral infections. However, discoveries in human viral infections have revealed unexpected findings that have enlarged the understanding of miRNA function within mammalian cells.

The role of miRNAs in modulating the response to hepatotrophic virus infection has been studied most extensively in the setting of hepatitis C virus (HCV) infection, the most common etiologic agent

miRNAs and HCC

miRNAs contribute to oncogenesis by mechanisms including decreased expression of tumor suppressor genes (oncomiRNAs) or, alternatively, as tumor suppressor genes targeting an oncogenic mRNA transcript for destruction (tumor suppressor miRNAs).⁷⁰

miRNA encoding genes frequently are located at sites of DNA deletion or amplification in malignancy,⁷¹ and although an association of miRNAs with cancer was demonstrated earlier in the setting of loss of miR15 and miR16 expression in chronic lymphocytic

miRNAs as Biomarkers of Liver Injury

Serum levels of alanine aminotransferase (ALT) along with aspartate aminotransferase (AST) are the primary serum biomarker of parenchymal liver injury in a variety of clinical scenarios.⁸¹ However, significant limitations exist to the use of aminotransferases as biomarkers of liver injury. First, elevations in serum aminotransferases can reflect nonhepatic injury (particularly skeletal muscle injury) and thus complicate noninvasive assessement of hepatic injury. Second, in situations such as

miRNAs as Biomarkers for HCC

Cirrhosis, regardless of the cause, is a significant risk factor for HCC formation, and the early detection of tumors is an important challenge. Current recommendations include ultrasound imaging every 6 to 12 months, which carries significant cost, has imperfect sensitivity and specificity, and are not available to all patients. Recent data suggest that serum miRNA analysis may be effective to detect HCC. Using a murine MYC-induced HCC model, serum miRNA analysis revealed altered patterns of

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Cited by (95)

Hepatocellular carcinoma and miRNAs: An in silico approach revealing potential therapeutic targets for polyphenols
2022, Phytomedicine Plus
Identifying innovative and effective therapeutic agents is imperative for treating hepatocellular carcinoma (HCC). Natural phytochemical compounds may be a feasible glimmer of hope as more than 8,000 phenolic structures are currently known, and several of them are efficient in treating different types of cancer.
MicroRNAs can modulate tumor cell response to growth signals, apoptosis and replication rates, new blood vessel formation, tissue invasion, and dissemination. We disclosed herein how phenolic compounds, influencing miRNAs-regulated genes, may exert their antitumor activities.
After a systematic review of the literature, we applied distinct in silico tools and approaches to query miRNA expression after treatment with polyphenols, determined some of the miRNA effects over target genes, elaborated protein networks and enriched their pathways, as well as presented differentially expressed genes (DEGs) found in HCC patients. Our predictions were corroborated by several in vitro and in vivo experimental studies that we presented and discussed.
Phytochemicals such as berberine, curcumin, EGCG, luteolin, and quercetin are promising candidates capable of regulating different miRNAs while exerting their antitumoral effects through distinct molecular mechanisms. MiRNAs such as miRNA-122 and -34a deserve deep investigations, as they were found to be over and down-expressed by more than one polyphenol. MiRNA-regulated genes took part in molecular mechanisms such as cell death, through p53, bcl-2, and SMAD modulation; energy metabolism, by regulating PI3K/Akt pathway; antiproliferative events, mediated by Ras, c-Kit, and β-catenin; and epigenetics events, involving SIRT, HDAC, and DNMT family members. Tumor microenvironment modulation, by NOTCH1 and VEGFA, is also a potential mechanism related to polyphenols’ effects. We reported that polyphenols have specific drug ability and anticancer biological activities. Among the DEGs, 4 of them (e.g., EZH2, HRAS, STMN1, VEGFA), are candidate genes for miRNA modulation. The expression profile of gene subsets that are frequently altered in HCC patients was also characterized.
The capacity of polyphenols to regulate miRNA actions may have a significant impact on the treatment of liver tumors; experimental and clinical studies dedicated to confirming our findings are further needed.
miR-190 promotes HCC proliferation and metastasis by targeting PHLPP1
2018, Experimental Cell Research
Citation Excerpt :
Some miRNA molecules can regulate the expression of multiple target genes to affect many cellular processes. However, the expression of a single gene can also be regulated by multiple miRNAs [11–13]. Some miRNAs promote tumour development by inhibiting antioncogene expression; however, some miRNAs also play a role in tumour inhibition by inhibiting oncogene expression.
miRNAs regulate gene expression and enable clinicians to distinguish between benign and malignant tissues in cancers. PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1) is known to be a tumour suppressor. A lentiviral overexpression system was used to stably express miR-190, leading to the enhancement of hepatocellular carcinoma (HCC) proliferation and metastasis as a result of inhibited PHLPP1 expression. The results showed that stable miR-190 expression increased the expression of EMT-related proteins (Snail and TCF8/ZEB1) as well as the phosphorylation of Akt at Ser473 and the expression of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1). However, restoring PHLPP1 expression counteracted the effects of miR-190 on HCC proliferation, migration and invasion. The results of the animal experiments showed that miR-190 improved the HepG2 cell tumour formation and lung metastasis ability. Stable miR-190 overexpression leads to the downregulation of PHLPP1 protein expression. miR-190 has potential as a target in the treatment and diagnosis of HCC.
Coptisine from Rhizoma coptidis exerts an anti-cancer effect on hepatocellular carcinoma by up-regulating miR-122
2018, Biomedicine and Pharmacotherapy
With increasing incidence and mortality, hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. In this study, microRNA-122 (miR-122) mimics and relevant control oligonucleotides were transfected into HepG2 cells in vitro, followed by coptisine (COP) and sorafenib treatments. Cell proliferation, migration, and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay, wound-healing assay, Hoechst 33258 staining and flow cytometry, respectively. Histopathology and miR-122 were analyzed by haemotoxylin and eosin (H&E) staining and real-time RT-PCR, respectively; whereas, the relevant protein expressions were detected by western blot. In vivo, COP enhanced the expression of miR-122 by 160% compared to control in male BALB/c nude mice; COP not only protected the liver morphology but also showed a significant anti-cancer effect. Further, there was no remarkable difference between the tumor weights in the COP and sorafenib groups, but there was a striking difference to the tumor control group (p < 0.05). Hence, COP inhibited the proliferation, migration and promoted apoptosis of HCC cells; moreover, it inhibited the tumor growth in nude mice by up-regulating the expression of miR-122.
Serum levels of miRNA in patients with hepatitis B virus-associated acute-on-chronic liver failure
2018, Hepatobiliary and Pancreatic Diseases International
Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum miRNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.
Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to 30 chronic asymptomatic HBV carriers as controls. The miRNAs expressions were measured by real-time quantitative PCR (q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed miRNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.
Real-time q-PCR indicated that serum miR-146a-5p, miR-122-3p and miR-328-3p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na⁺, INR, gastrointestinal bleeding and miR-122-3p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na⁺ − 1.72 × INR − 4.963 × gastrointestinal bleeding (Yes = 0; No = 1)−0.278 × (miR-122-3p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve (AUROC) was 0.847.
Expression levels of these miRNAs (miR-146a-5p, miR-122-3p and miR-328-3p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.
MicroRNAs link chronic inflammation in childhood to growth impairment and insulin-resistance
2018, Cytokine and Growth Factor Reviews
Citation Excerpt :
To date, miRNAs have been predicted to target and control the expression of at least 30% of the entire mammalian genome [10]. Since their discovery, miRNAs have been found to be involved in multiple pathophysiological networks [11,12] and in the pathogenesis of a broad spectrum of human diseases, including cancer and inflammatory diseases [13–18]. The molecular rules governing the targeting of each miRNA to individual genes have been documented [19,20].
MicroRNAs are involved in multiple pathophysiological networks and in the pathogenesis of a broad spectrum of human disorders, including cancer and inflammatory diseases.
Impaired linear growth is encountered in children with chronic inflammatory conditions such as cystic fibrosis, inflammatory bowel diseases, juvenile idiopathic arthritis, celiac disease and in subjects born intrauterine growth restricted/small for gestational age.
Children with inflammatory conditions may also be at risk of developing insulin resistance as a result of the inflammatory process and concurrent therapy.
Chronic inflammation may lead to a continuum of abnormalities in the Growth hormone/Insulin-like growth factor 1 (GH/IGF-I) axis, including relative GH insufficiency, GH/IGF-I resistance due to down regulation of GH and IGF-I receptors, changes in GH and IGF-I bioavailability due to modifications of binding proteins, and/or impaired GH/IGF-I signaling.
The aim of this review is first to summarize the current knowledge concerning microRNAs involved in inflammation in the most relevant chronic inflammatory diseases in childhood, second to provide new insights into miRNA regulation of growth and insulin sensitivity mediated by the inflammatory processes. We evaluated single microRNAs involved in inflammation in the single conditions mentioned above and verified which had validated and predicted targets within the GH receptor, IGF-I type 1 receptor and insulin receptor interactomes.
The findings show a new link among inflammation, growth and insulin sensitivity mediated by miRNAs that warrants further research in the future.
Alterations in microRNA expression in the tissues of silver carp (Hypophthalmichthys molitrix) following microcystin-LR exposure
2017, Toxicon
In the field of toxicology, the relationship between microRNAs (miRNAs) and microcystin-LR (MC-LR) toxicity in fish is still poorly understood. In the present study, we used quantitative real-time PCR (qPCR) to examine the expression of 7 miRNAs (let-7b, miR-21, miR-122, miR-27b, miR-148, miR-125a, and miR-143) that play regulatory roles in biological processes such as signal transduction, apoptosis, cell cycle, and fatty acid metabolism. Expression patterns were assessed in the liver, spleen, and kidney of silver carp following 8, 24, and 48 h of exposure to MC-LR via intraperitoneal injection (50 or 200 μg/kg of body weight). The results of qPCR analysis showed that the expression of the 7 miRNAs was either upregulated or downregulated in response to MC-LR exposure. These results indicate that acute MC-LR exposure altered miRNAs expression profiles in the liver, spleen, and kidney of silver carp, suggesting that miRNAs may be involved in MC-LR toxicity.

View all citing articles on Scopus

: Supported by Grants HL-38180, DK-52574, and DK-52560 and by a Fellow to Faculty transition award from the Foundation for Digestive Health and Nutrition.

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Review ArticleMicroRNAs and liver disease

Section snippets

miRNA Biogenesis

miRNA Analysis and Bioinformatics

Hepatic miRNAs as Metabolic Modulators and Their Importance in NAFLD

miRNAs and Hepatitis C Virus (HCV)

miRNAs and HCC

miRNAs as Biomarkers of Liver Injury

miRNAs as Biomarkers for HCC

Cell

Cell Metab

Trends Biochem Sci

Trends Cell Biol

Cell

Cell Metab

J Hepatol

J Lipid Res

J Biol Chem

Biochem Biophys Res Commun

J Lipid Res

J Biol Chem

Cell Host Microbe

Lab Invest

J Hepatol

Cell Stem Cell

J Biomol Screen

Gastroenterology

J Biol Chem

Biochem Biophys Res Commun

Gastroenterology

J Hepatol

Cell

Toxicology

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

Nature

MicroRNA in the immune system, microRNA as an immune system

Immunology

The microRNA registry

Nucleic Acids Res

MicroRNA expression profiling using microarrays

Nat Protoc

Desperately seeking microRNA targets

Nat Struct Mol Biol

Silencing of microRNAs in vivo with “antagomirs.”

Nature

miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1

RNA Biol

Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver

Nucleic Acids Res

Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression

Hepatology

Integration of microRNA miR-122 in hepatic circadian gene expression

Genes Dev

MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis

Science

miR-33 links SREBP-2 induction to repression of sterol transporters

Proc Natl Acad Sci U S A

Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA

Science

Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122

J Virol

Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection

Science

Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma

J Am Chem Soc

MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins

Hepatology

Review Article
MicroRNAs and liver disease