MiR-122

Last updated

mir-122 microRNA precursor
MiR-122 structure and sequence conservation.jpg
Predicted secondary structure and sequence conservation of mir-122
Identifiers
Symbolmir-122
Rfam RF00684
miRBase MI0000442
miRBase family MIPF0000095
Other data
RNA type Gene; miRNA
Domain(s) Eukaryota
GO GO:0035195
SO SO:0001244
PDB structures PDBe

miR-122 is a miRNA that is conserved among vertebrate species. miR-122 is not present in invertebrates, and no close paralogs of miR-122 have been detected. [1] miR-122 is highly expressed in the liver, where it has been implicated as a regulator of fatty-acid metabolism in mouse studies. Reduced miR-122 levels are associated with hepatocellular carcinoma. miR-122 also plays an important positive role in the regulation of hepatitis C virus replication.

Contents

Expression and regulation

miR-122 was originally identified by cloning of tissue-specific microRNAs in mouse. [2] The liver-specific expression of miR-122 is conserved in zebrafish. [3] miR-122 expression increases during embryogenesis until it constitutes 72% of total miRNA in adult human liver, making it one of the most highly expressed miRNAs in any tissue. [4] In humans, miR-122 is encoded at a single genomic locus in chromosome 18. The primary miR-122 transcript (pri-miR-122) is a long non-coding RNA. Transcription is regulated by HNF4α. [5] The miR-122 hairpin precursor consensus shown here is predicted based on base pairing and cross-species conservation. The mature sequence is excised from the 5' arm of the hairpin. [2] [6]

There is evidence that miR-122 is regulated by Rev-ErbA alpha which is involved in circadian gene expression, suggesting that miR-122 is a circadian metabolic regulator. miR-122 regulates the expression of several mRNA molecules that are important in the circadian cycle, such as PPARβ/δ. [7] Mature miR-122 is subject to modification by the poly(A) polymerase GLD-2, which adds a single adenosine to the miRNA 3' end. This results in an increase in miR-122 stability. [8]

Targets

miR-122 regulates the synthesis of the protein CAT-1 by binding to sites in the mRNA 3'UTR such that translation is repressed and the mRNA is targeted to P bodies. This repression can be relieved by the protein HuR, which is released from the nucleus under conditions of cell stress and binds to the CAT-1 3'UTR. The HuR interaction leads to release of the mRNA from the P bodies and resumption of active translation. [9]

A number of other miR-122 targets, including CD320, AldoA and BCKDK, have been identified by microarray analysis of changes in mRNA expression in the liver of mice treated with miR-122 inhibitors. [10] [11] [12] The overall effect of miR-122 inhibition is to reduce the plasma cholesterol level, although the pathways involved in this regulation have not been fully elucidated. miR-122 also regulates systemic iron homeostasis via the target mRNAs Hjv and Hfe. [13] miR-122 inhibition in mice or primates does not result in any detectable liver toxicity. [14]

Role in cancer

miR-122 levels are frequently reduced in hepatocellular carcinoma (HCC) compared to normal liver, and low miR-122 levels correlate with poor prognosis. [15] [16] Overexpression of miR-122 reduces tumorigenic properties in HCC cell lines, suggesting that it functions as a tumor suppressor gene, and increases the response of cells to the chemotherapeutic drugs sorafenib and doxorubicin. [17] [18] Several miR-122 target genes have been implicated in tumorigenesis, including ADAM10, IGF1R, CCNG1 and ADAM17. [17] [18] [19]

Innate Immunity

Recent studies demonstrated that miR-122 may directly regulate different aspects of the interferons (IFNs) signaling pathway [20] [21] to enhanced induction of anti-viral genes and inhibition of various virus. [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] Moreover, miR-122 have been shown to target various genes, [31] [32] [29] [33] [28] resulting in enhancement of IFN signaling and subsequent antiviral innate immunity. [31] [27] Interferons (IFNs, includes type I and III interferon) treatment leads to a significant reduction in the expression of the liver-specific miR-122. [21] [34] [35] [36] [28] HepG2 cells with overexpressed microRNA-122 mount an effective antiviral interferon response and innate immune response to hepatitis C virus (HCV), other RNA viruses and viral mimetics (e.g. poly(I:C)). [22]

Regulation of HCV

Recent studies have shown that replication of hepatitis C virus (HCV) is dependent on miR-122 expression. [37] miR-122 regulates HCV by binding directly to two adjacent sites close to the 5' end of HCV RNA. [38] Although these experiments were conducted using genotype 1a and 1b HCV RNA, the miR-122 binding sites are highly conserved across different genotypes, and miR-122 is also required for replication of infectious type 2a HCV. [39] As miRNAs generally function to repress gene expression by binding to 3'UTR sites, this positive regulation of viral replication via a 5'UTR represents a novel function for miR-122. The mechanism of regulation is not yet clear. miR-122 stimulates translation of HCV RNA, but not to a sufficient extent to explain its effects on viral replication, indicating that a second stage of the viral replication cycle must also be regulated. [40] [41] HCV RNA synthesis is not affected by miR-122, suggesting that regulation of other processes such as RNA stability may occur. [42] [43] The extent to which the miRNA-induced silencing complex (miRISC) is involved in this regulation has not been fully determined. The Argonaute proteins (Ago1–4), which are essential for miRNA-directed repression, appear to be necessary for miR-122 to regulate HCV, [44] although miR-122 overexpression may overcome this requirement. [45] The crystal structure of Ago2:miR-122 bound to the miR-122 binding site at the 5'-end of the HCV genome, in combination with functional experiments, suggests that the viral RNA has evolved to maximize protection from cytoplasmic exoribonucleases by altering the molecular behavior of Ago2. [46] Another miRISC component, the DEAD-box RNA helicase DDX6, does not play a role in miR-122-facilitated HCV replication. [47]

The existing HCV therapy of PEG-IFNα plus ribavirin is poorly tolerated and frequently ineffective, [48] [26] so there is an urgent need for new drugs, and miR-122 inhibitors are an attractive possibility. The association between low miR-122 levels and hepatocellular carcinoma suggests that caution will be necessary when testing miR-122 inhibitors, and that long-term treatment might be undesirable. However, miR-122 is a promising target as it can be very selectively and effectively inhibited with antisense oligonucleotides, and as it is a conserved host factor it is hoped that the virus would not be able to acquire resistance mutations to an anti-miR-122 therapeutic. Moreover, engineering HepG2 cells to express miR-122 (HepG2-HFL cell, HepG2 cells expressing miR-122) mount an effective antiviral interferon-lambda (IFNλ) based innate immune response to hepatitis C virus (HCV) infection. [22] [25] HepG2 cells (stably expressing miR-122) produced a more robust IFN Response (type I and type III interferons) when challenged with other RNA viruses [ IAV-ΔNS1 and SeV ] and viral mimetics than Huh-7 and Huh-7.5 cells. HCV Induces an IFN-λ (IL28 and IL29), ISG, and Cytokine Response in these HepG2 cells with stably expressing miR-122. [22] [23] [24] [31] [27]

Inhibitor miravirsen

As of 2017, Santaris Pharma was developing miravirsen, a locked nucleic acid-based antisense oligonucleotide that inhibits miR-122, as a potential treatment for HepC. [49]

Use as a biomarker

miR-122 has recently been explored as a potential biomarker for various hepatic conditions. A change in levels of miR-122 in the blood has been confirmed as an indicator for viral-, alcohol- and chemical-induced liver injury [50] [51] [52] as well as Transplant rejection after Liver transplantation. [53] [54] This change is noted before increased amino-transferase activity, making it an early indicator of liver disease and hepatocellular injury of liver grafts prior to liver transplantation. [53] [55]

There is a great deal of research into the use of miR-122 as a biomarker for hepatitis C. While some studies dispute its efficacy for diagnosing Hep C, [56] other research indicates that it may be useful in diagnosing specific forms of hepatitis. [57] In addition, decreased levels of miR-122 in liver biopsies have been linked to a strain of hepatitis C that is resistant to interferon therapy. [26]

miR-122 has also been suggested as a biomarker for hepatectomy-induced liver injury in patients with hepatocellular carcinoma. [58]

It is important to note that detection of miR-122 and other microRNAs in Body fluid like blood can be interfered by heparin contaminated. The commonly used anticoagulant heparin profoundly inhibits the by reverse transcription polymerase chain reaction (RT-PCR) used for microRNA quantification. [59] [60]

Related Research Articles

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<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

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<span class="mw-page-title-main">Hepatocellular carcinoma</span> Medical condition

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<span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

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