miR-122

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mir-122 microRNA precursor
MiR-122 structure and sequence conservation.jpg
Predicted secondary structure and sequence conservation of mir-122
Identifiers
Symbol mir-122
Rfam RF00684
miRBase MI0000442
miRBase family MIPF0000095
Other data
RNA type Gene; miRNA
Domain(s) Eukaryota
GO 0035195 0035068
SO 0001244

miR-122 is a miRNA that is conserved between vertebrate species. miR-122 is not present in invertebrates, and no close paralogs of miR-122 have been detected.[1] miR-122 expression is specific to 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.

Expression and regulation[edit]

miR-122 was originally identified by cloning of tissue-specific microRNAs in mouse, where its expression is restricted to the liver.[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]

miR-122 targets[edit]

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[edit]

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]

Regulation of HCV[edit]

Recent studies have shown that replication of hepatitis C virus (HCV) is dependent on miR-122 expression.[20] miR-122 regulates HCV by binding directly to two adjacent sites close to the 5' end of HCV RNA.[21] 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.[22] 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.[23][24] HCV RNA synthesis is not affected by miR-122, suggesting that regulation of other processes such as RNA stability may occur.[25][26] 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,[27] although miR-122 overexpression may overcome this requirement.[28] Another miRISC component, the DEAD-box RNA helicase DDX6, does not play a role in miR-122-facilitated HCV replication.[29]

The existing HCV therapy of PEG-IFNα plus ribavirin is poorly tolerated and frequently ineffective, 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.

Inhibitor - Miravirsen[edit]

Santaris Pharma have developed a locked nucleic acid-based antisense oligonucleotide that is delivered to the liver and effectively inhibits miR-122 following intravenous injection without inducing liver toxicity.[30] This molecule reduced HCV viremia in a small-scale trial in chimpanzees.[31] The inhibitor is known as miravirsen and is in phase II clinical trials with the results expected in early 2012.[32]

Miravirsen is currently undergoing Phase IIa trial with preliminary data presented on November 2011 at The Liver Meeting showing promising results from a group of chronic HCV genotype 1 infection patients. Patients were randomly assigned to placebo groups or one of the three multiple ascending dose groups (3 mg/kg, 5 mg/kg, 7 mg/kg of miravirsen). The naïve patients were given 5 weekly doses of miravirsen via subcutaneous injection for four weeks, and 4 out of 9 patients receiving the highest dose (7 mg/kg) exhibited significant decrease in Hepatitis C virus RNA (p<0.001). The result was sustained even 10 weeks after the last miravirsen administration.[33] Further trials testing for the safety and pharmokinetics of miravirsen will also be conducted in other countries such as Germany and Netherlands.[32]

Final results are being presented in April 2012.[34][35][36][37]

Use as a Biomarker[edit]

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 liver disease.[38][39] This change is noted before increased amino-transferase activity, making it a preferable indicator for liver disease. This study also suggested that miR-122 could be a “novel, predictive and reliable blood marker for viral-, alcohol- and chemical-induced liver injury.” [5]

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,[40] other research indicates that it may be useful in diagnosing specific forms of Hepatitis. For instance, decreased levels of miR-122 have been linked to a strain of Hepatitis C that is resistant to interferon therapy.[41] In this case, measuring miR-122 levels in the bloodstream of Hepatitis C positive patients would enable more accurate and personalized therapy for their disease.

miR-122 has also been suggested as a biomarker for hepatectomy-induced liver injury in patients with hepatocellular carcinoma. [42]


References[edit]

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Further reading[edit]

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]

  1. ^ Zeng C, Wang R, Li D, Lin XJ, Wei QK, Yuan Y, Wang Q, Chen W, Zhuang SM (2010). "A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma.". Hepatology 52 (5): 1702–12. doi:10.1002/hep.23875. PMID 21038412. 
  2. ^ Shea CM, Tzertzinis G (2010). "Controlled expression of functional miR-122 with a ligand inducible expression system.". BMC Biotechnol 10 (1): 76. doi:10.1186/1472-6750-10-76. PMC 2976731. PMID 20961424. 
  3. ^ Stilling G, Sun Z, Zhang S, Jin L, Righi A, Kovācs G, Korbonits M, Scheithauer BW, Kovacs K, Lloyd RV (2010). "MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas.". Endocrine 38 (1): 67–75. doi:10.1007/s12020-010-9346-0. PMID 20960104. 
  4. ^ Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H, Fei M, Sun S (2010). "Plasma MicroRNA-122 as a Biomarker for Viral-, Alcohol-, and Chemical-Related Hepatic Diseases.". Clin Chem 56 (12): 1830–8. doi:10.1373/clinchem.2010.147850. PMID 20930130. 
  5. ^ Xu H, He JH, Xiao ZD, Zhang QQ, Chen YQ, Zhou H, Qu LH (2010). "Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development.". Hepatology 52 (4): 1431–42. doi:10.1002/hep.23818. PMID 20842632. 
  6. ^ Burchard J, Zhang C, Liu AM, Poon RT, Lee NP, Wong KF, Sham PC, Lam BY, Ferguson MD, Tokiwa G, Smith R, Leeson B, Beard R, Lamb JR, Lim L, Mao M, Dai H, Luk JM (2010). "microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma.". Mol Syst Biol 6 (1): 402. doi:10.1038/msb.2010.58. PMC 2950084. PMID 20739924. 
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  11. ^ Qian J, Zhai A, Kao W, Li Y, Song W, Fu Y, Chen X, Zhang Q, Wu J, Li H, Zhong Z, Ling H, Zhang F (2010). "Modulation of miR-122 on persistently Borna disease virus infected human oligodendroglial cells.". Antiviral Res 87 (2): 249–56. doi:10.1016/j.antiviral.2010.05.011. PMID 20561966. 
  12. ^ Young DD, Connelly CM, Grohmann C, Deiters A (2010). "Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma.". J Am Chem Soc 132 (23): 7976–81. doi:10.1021/ja910275u. PMID 20527935. 
  13. ^ Chang Y, He XX, Li PY, Lin JS (2010). "[MiR-122 regulates the expression of PEG10 in hepatoma cell lines]". Zhonghua Gan Zang Bing Za Zhi 18 (4): 288–91. doi:10.3760/cma.j.issn.1007-3418.2010.04.013. PMID 20460050. 
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  15. ^ Lee TC, Lin YL, Liao JT, Su CM, Lin CC, Lin WP, Liao CL (2010). "Utilizing liver-specific microRNA-122 to modulate replication of dengue virus replicon.". Biochem Biophys Res Commun 396 (3): 596–601. doi:10.1016/j.bbrc.2010.04.080. PMID 20412785. 
  16. ^ Pfeffer S, Baumert TF (2010). "Antagonizing microRNA-122 and treatment of hepatitis C virus infection.". In Kowdley, Kris; McCaughan, Geoffrey; Trautwein, Christian. Hepatology 51 (4): 1461–3. doi:10.1002/hep.23573. PMID 20373371. 
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