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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 116-121

MicroRNA and liver diseases


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine at Ministry of Health, Sherbeen, Dakahlia, Egypt

Date of Submission08-Aug-2018
Date of Decision28-Oct-2018
Date of Acceptance30-Oct-2018
Date of Web Publication25-Mar-2020

Correspondence Address:
Ahmed A Abdalwahab
Sherbeen, Dakahlia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_227_18

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  Abstract 

Objective
The aim was to review and update the relationship between microRNA and various liver diseases such as viral hepatitis, liver cirrhosis, alcoholic liver disease, liver fibrosis, and hepatocellular carcinoma.
Background
MicroRNAs play an important role in miscellaneous cellular process including development, immunity, cell-cycle control metabolism, viral or bacterial disease, stem cell differentiation, and oncogenesis.
Materials and methods
Medline databases, including PubMed, Medscape, Science Direct, and EMF-Portal, and all materials available on the internet from 2004 to 2018 were searched. The initial search presented many articles that studied the microRNA and its relation to various liver diseases. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls mentioned, adequate information provided, and assessment measures defined. Comparisons were made by structured review with the results tabulated.
Findings
MicroRNAs are recognized to play an important role in diagnosis, prognosis, and treatment in various liver diseases.
Conclusion
The significance of miRNA regulation in different physiological and pathological conditions is becoming increasingly visible and undeniable. A number of studies have reported the crucial roles that miRNAs exert along the onset and development of various pathologies including acute and chronic liver diseases such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and also hepatocellular carcinoma.

Keywords: MicroRNA development, MicroRNA in diagnosis of liver diseases, MicroRNA in treatment of liver diseases


How to cite this article:
Abdel-Atti EA, Alshayeeb AI, Abdalwahab AA. MicroRNA and liver diseases. Menoufia Med J 2020;33:116-21

How to cite this URL:
Abdel-Atti EA, Alshayeeb AI, Abdalwahab AA. MicroRNA and liver diseases. Menoufia Med J [serial online] 2020 [cited 2020 Mar 30];33:116-21. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/116/281277




  Introduction Top


MicroRNAs are 20–22-nucleotide-long noncoding RNAs that were first described in 1993. MicroRNAs play an important role in miscellaneous cellular process including development, immunity, cell-cycle control metabolism, viral or bacterial disease, stem cell differentiation, and oncogenesis[1]. MicroRNAs have emerged as fine regulators of gene function and their presence in various body fluid identifies them as attractive potential biomarkers of diseases. Serum/plasma miR-122 and miR-155 may serve as biomarkers of liver damage and inflammation. An increase in circulating miR-122 correlates with liver damage regardless of the etiology of hepatocyte injury. miR-155 is a candidate biomarker of liver inflammation[2]. Although previous standard therapy of hepatitis C virus (HCV) was pegylated interferons-α in combination with ribavirin, success of the therapy depends upon the viral load before and during therapy and the genotype of the virus. Despite therapy, half of the patients fail to completely eradicate the virus, and both interferon and ribavirin are expensive and can cause severe adverse effects limiting their clinical utility[3]. MicroRNAs are important and fundamental modulators of mRNA and protein expression. In future, purposeful modulation of these levels and effects will, more likely than not, become important in the therapeutic armamentarium of hepatic and other diseases[4]. MicroRNA-23b was shown to play an important role in the termination of liver regeneration by activating TGF-β1 and Smad3 signaling in rats, and the upregulation of miR-23b inhibited TGF-β1-driven apoptosis[5]. It has been suggested that many of the miRNA changes that occur during hepatocarcinogenesis do so early, so that many changes that predispose to hepatocellular carcinoma (HCC) have already taken place in liver cirrhosis and other premalignant lesions. Subsequent changes in the miRNA expression in the transition from cirrhosis to HCC seem to be much less marked[6]. Numerous studies indicate that loss of miRNAs can contribute to liver tumorigenesis. It was shown that ectopic expression of a single miRNA, miR-26a, could reverse HCC progression in a mouse model of liver cancer. Disturbed expression of miR-26a dysregulates cell cycle and proliferation as seen in liver cancer cells, but inhibition of miR-26 through therapeutic modulation could prevent these devastating effects[7]. Increasing evidence suggests that miRNAs are key regulators of hepatic fibrogenesis, in particular by regulating gene expression in hepatic stellate cells; expression of the miR-199 and families has been correlated with progression of liver fibrosis[8]. Many studies have identified several miRNAs as key players in virus-host interactions, regulating virus replication and pathogenesis during HCV infection. The most abundant miRNA in the liver, miR-122 is regulated by specific, liver-enriched transcription factor, hepatocyte nuclear factor-4α, and is responsible for liver homeostasis[9]. Alcoholic liver disease, alcoholic hepatitis, and cirrhosis represent a major segment of liver diseases worldwide. A report by Dolganiuc et al.[10] analyzed the miRNA expression profile in a murine model of alcoholic liver disease. Liver samples from mice fed an ethanol-containing diet showed features of alcoholic steatohepatitis and had an increased expression of miR-320 and miR-486 and decreased expression for several miRNAs, including miR-27b[11].

The aim of this study was to show the important relationship between MicroRNAs and various liver diseases.


  Materials and Methods Top


The guideline for conducting this review was according to guidance developed by the Center for Review and Dissemination. It was used to assess the methodology and outcome of the studies.

Search strategy

We reviewed papers on microRNAs from Medline databases, including PubMed, Medscape, and Science Direct, and also materials available on the Internet. In addition, we examined references from the specialist databases EMF-Portal (http://www.emf-portal.de) and reference lists in relevant publications. The search was performed in the electronic databases from 2004 to 2018.

Study selection

  1. All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria: Published in English language
  2. Published in peer-reviewed journals.


Data extraction

Data from each eligible study were independently abstracted in duplicate using a data collection form that captures information on study characteristics, interventions, quantitative results reported for each outcome of interest, and conclusion and comments on each study made.

There was heterogeneity in the collected data. It was not possible to perform a meta-analysis owing to lack of a database. Significant data were collected. Thus, a structured review was performed, with the results tabulated.

The analyzed publications were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for evidence-based medicine in addition to the Evidence Pyramid.

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.


  Results Top


Study selection and characteristics

In total, potentially relevant publications were identified. All of these articles were included in the review as they were deemed eligible by fulfilling the inclusion criteria.

In the study by Hassan and Al-Olayan[5], to identify the effect of curcumin on liver fibrosis through regulating the miRNA expression in the treated mice with CM and the control groups (normal and fibrotic liver), the authors intraperitoneally administered CCL4 in olive oil or olive oil for 12 weeks as the study design for the three groups. Mice were killed at 4, 8, or 12 weeks, and then the degree of mouse liver fibrosis was determined by microscopy. Expression of mir-199 and mir -200 and their targeted genes were quantified by using real-time PCR. A significant overexpression of miR-199a, 199a*, 200a, and 200b was associated with the progression of liver fibrosis in group 1 compared with the control group [Table 1]. Moreover, in the same group, there was an upregulation in the a1-procollagen gene expression. To reveal the effect of CM on the miR-199a, miR-199a*, miR-200a, and miR-200b, they studied the involvement of these miRNAs in the modulation of fibrosis-related gene by studying the expression of fibrosis-related genes, including a matrix-degrading complex comprising a1 procollagen, matrix remodeling complex including MMP13, and tissue inhibitors of metalloproteinases-1. In addition, over-expression of miR-199a, miR-199a*, miR-200a, and miR-200b was associated with significant upregulation in fibrosis-related genes, a1 procollagen, and tissue inhibitors of metalloproteinases-1 compared with control group. Finally, in group 2, the expression levels of miR-199a and miR-199a* were nearly equal to the level of the normal group.
Table 1: The primer sequences

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In a study by Kerr et al.[12], in a mouse model of acetaminophen-induced liver injury, the utility of miRNAs were assessed. Acetaminophen-induced liver injury resulted in a significant increase in microarray-determined serum concentration of hepatocyte-specific miRNAs including mir-122 and mir-192. Increased abundance of these miRNAs in serum was dose dependent and occurred within 1 h after acetaminophen exposure, before increases in serum transaminase concentration. A similar study investigating the utility of miRNAs as biomarkers of liver, muscle, or brain injury using a rat model revealed that miR-122 and miR-133a were specific serum markers of liver and muscle injury, respectively, whereas aspartate aminotransferase and alanine aminotransferase were elevated in experimentally induced injury to either tissue.

In Varnholt[6], gene expression profiles of miRNAs are much less detailed in cholangiocarcinomas than in HCCs. Cholangiocarcinomas are highly chemoresistant biliary malignancies with poorly understood mechanisms of growth regulation. Most studies thus far have utilized cell cultures or rodent models. In cholangiocarcinomas, upregulated oncomiRs are miR-141, miR-21, miR-23a, miR-27a, let-7a, and miR-200b, whereas downregulated tumor suppressor miRNAs are miR-29b and miR-370. MiR-141 is highly overexpressed in malignant cholangiocytes and may target the CLOCK gene, which regulates circadian rhythms and can act as a tumor suppressor. Inhibition of miR-141 decreases cell growth of cholangiocarcinoma cells. Let-7a and miR-21 have been found to be overexpressed in both HCCs and cholangiocarcinomas [Table 2].
Table 2: Frequently dysregulated microRNAs in hepatocellular carcinomas

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Bala et al.[2] studied specific miRNA signatures in HCC formation and progression that could be exploited as potential cancer biomarkers. In brief, miR-18, miR-21, miR-221, miR-222, miR-224, miR-373, and miR-301 were reported to be upregulated, whereas miR-122, miR-125, miR-130a, miR-150, miR-199, miR-200, and let-7 family member were found to be downregulated in HCC. These miRNAs target the genes involved in cell cycle and cell death regulation, including cyclin-dependent inhibitors p27/CDKN1B and p57/CDKN1C, or the PI3K antagonist phosphatase and tensin homolog.


  Discussion Top


Several miRNAs have been identified in various studies to play a key role in regulating the virus replication and pathogenesis during HCV infection. miR-122 is the most abundant liver-specific miRNA and has been demonstrated by several studies to be required for HCV replication in infected cells. Sequestration of miR-122 in liver cell lines strongly reduced HCV translation, whereas addition of miR-122 stimulated HCV translation in liver cell lines. A study on liver biopsies of patients with chronic hepatitis demonstrated that miR-122 level in primary nonresponding subjects was lower than in early virological responding subjects, regardless of the viral genotype[3]. Humanmir-122 leads to accumulation of viral RNA during HCV infection, and was therefore suggested to positively interfere with viral replication. This explains why successful HCV infection depends on the presence of mir-122. Knocking down components of the miRNA pathways or mir-122 leads to reduced HCV replication. Other RNA viruses are sensitive to host miRNAs. Mouse mir-24 and mir-93 serve as host defense by targeting large protein (L protein) and phosphoprotein (P protein) genes of rhabdovirus vesicular stomatitis virus[20]. Although miR-122 is the best studied of the miRNAs to interact with HCV, it is not unique. miR-199a also recognizes sequences in the NCR of HCV and downregulates HCV RNA replication. MicroRNA-196 also contains within its seed sequence a region complementary to sequences in HCV, and both inhibit HCV expression and downregulate Bach1. MicroRNA-196 is also one of eight miRNAs upregulated in response to interferon signaling. It is also worth noting that miR-122-associated suppression of HO-1 was associated with a decreased replication of hepatitis B virus (HBV). In other words, although targeting miR-122 expression may become a relevant strategy to attenuate HCV replication, the data suggest that such a strategy would increase HBV replication. This consideration would be important in coinfected individuals. In other work (expanded on in subsequent paragraphs), findings from subjects with HBV and HCC suggest that miR-152 is frequently downregulated in and inversely correlated with the expression of DNA methyltransferase I. The findings also indicated alterations in global methylation profiles suggesting that the epigenetic changes associated with alterations in miR-152 expression may be useful predictors of HCC in patients with chronic HBV infection[12]. A differential miRNA expression pattern was found in the livers of HBV-infected and HCV-infected individuals with hepatocellular cancer. A total of 19 miRNAs were clearly differentiated between HBV and HCV groups, out of which 13 miRNAs were downregulated in the HCV group, whereas six showed a decreased expression in the HBV group. Some of the differentially regulated miRNAs between the HCV and HBV groups were miR-190, miR-134, miR-151, miR-193, miR-211, and miR-20. Interestingly it was shown that pathway analysis of targeted genes using infection-associated miRNAs could differentiate the genes into two groups. For instance, in HBV-infected livers, pathways related to cell death, DNA damage, recombination, and signal transduction were activated, and those related to immune response, antigen presentation, cell cycle, proteasome, and lipid metabolism were activated in HCV-infected livers[8]. Specific changes in miRNA expression patterns have been shown in HCC as compared with adjacent normal liver tumor tissues, or liver cirrhosis that correlated with the disease outcome. Using a human miRNA microarray, Murakami et al.[17] analyzed the miRNA expression profiles in 25 pairs of HCC and adjacent nontumorous tissue and nine additional chronic hepatitis specimens. This study found out that seven mature miRNAs and one precursor miRNA exhibited significant differential expression patterns between the HCC and nontumorous tissue samples, with miR-18, precursor miR-18, and miR-224 upregulated in HCC samples and miR-199a, miR-195, miR-199a, miR-200a, and miR-125a downregulated in HCC samples[3]. In human NAFLD, 23 miRNAs regulating cell proliferation, apoptosis, inflammation, oxidative stress and metabolism were either overexpressed or underexpressed. Changes in miRNAs in the metabolic syndrome that support NAFLD and nonalcoholic steatohepatitis (NASH) have recently been reviewed in relevance to potential therapeutic strategies[21]. Several microRNAs have been extensively proven and accepted to be potent regulators in the pathogenesis of NAFLD. The expression of miR-34ain human liver has clearly been confirmed to have a crucial role in regulating liver inflammation. Thus, it is associated with significantly increased severity in NAFLD. Moreover, serum miR-34a could distinguish NASH from simple steatosis and healthy individuals. However, the correlation between serum level of miR-34a and degree of liver inflammation has not been directly reported from past studies[22]. miRNA can be characterized as prognostic or diagnostic markers. Downregulation of the miRNA miR-let-7g, miR-22, miR-26, miR-29, miR-99a, miR-122, miR-124, miR-139, miR-14581, and miR-199b has been implicated in cell proliferation, apoptosis, angiogenesis, recurrence, shorter disease-free survival, and poor prognosis. In contrast, upregulation of miR-10b, miR-17-5p, miR-21, miR-135a, miR-155, miR-182, miR-221, and miR-222 has been associated with metastasis, angiogenesis, and poor prognosis. In addition, miRNA profiling classified HCC into three main clusters. These results indicate the potential value of miRNA detection for the prediction of survival in HCC[23].

Identification of a metastatic mechanism is important to improve the long-term survival of patients with HCC owing to its high rate of intrahepatic metastasis. However, the mechanism of miRNAs in HCC metastasis is poorly understood. Hurst and colleagues gave the term 'metastamir' to describe the set of miRNAs that participate in the metastatic cascade. In many cases, these miRNAs are specific for metastatic development and are not involved in tumorigenesis. Some miRNAs, such as miR-122 and let-7g, function as suppressors of metastasis. miR-122 significantly decreases the tumor volume and suppresses metastasis by reducing blood vessel formation. Recently, miR-142-3p was shown to suppress migration and invasion of a HCC cell line by directly and negatively regulating ras-related C3 botulinum toxin substrate 1, which is a regulator of cell migration and invasion[24]. Several miRNAs have been identified to play key roles in the development of steatosis and its progression to steatohepatitis, fibrosis, cirrhosis, and HCC. One of the most lipid-responsive miRNAs in the liver is miR-34a, which is heavily upregulated in mice kept on high-fat diet, and its expression levels in humans correlate with the severity of NASH. Overexpression of miR-34a results in hepatocellular apoptosis. A major target of miR-34a is the NAD-dependent deacetylase Sirtuin-1 (SIRT1), which has a key role in energy homeostasis by activating pivotal transcription factors such as peroxisome proliferator-activated receptor-alpha (PPAR_) and liver X receptor (LXR), whereas it has an inhibitory effect on PPAR-gamma coactivator-1alpha (PGC-1_), sterol regulatory element-binding protein 1c (SREBP1c), and farnesoid X receptor (FXR). Silencing of miR-34a restores the expression of SIRT1 and PPAR_, resulting in activation of the metabolic sensor AMP-activated protein kinase and the activation of various PPAR_ target genes, suggesting a fundamental role of miR-34a in the deregulation of lipid metabolism associated with NAFLD[25].


  Conclusion Top


The value of miRNAs as therapeutic targets is now widely recognized. Within 10 years, slightly more than 1000 human unique miRNAs have been discovered and await utility in clinical applications. For many of these, extensive investigations ex vivo suggest therapeutic opportunities in areas of unmet medical need; some of these have already been validated in clinically relevant animal models, and a few are in (pre) clinical development. It is increasingly evident that miRNAs play a novel and important role in regulation of gene expression. In recent years, research focusing on small molecules such as miRNAs has intensified to understand their role in health and disease. The excitement of exploring their regulatory potential will remain for years to come, given the observation that miRNAs could be ideal therapeutic targets for many diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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