Biology: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
Symbolmir-122
RfamRF00684
miRBaseMI0000442
miRBase familyMIPF0000095
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GO0035195
SO0001244
PDB structuresPDBe

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.

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]

References

  1. ↑ "miRBase". http://www.mirbase.org/index.shtml. 
  2. ↑ 2.0 2.1 "Identification of tissue-specific microRNAs from mouse". Current Biology 12 (9): 735–739. April 2002. doi:10.1016/S0960-9822(02)00809-6. PMID 12007417. 
  3. ↑ "MicroRNA expression in zebrafish embryonic development". Science 309 (5732): 310–311. July 2005. doi:10.1126/science.1114519. PMID 15919954. Bibcode: 2005Sci...309..310W. 
  4. ↑ "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 Biology 1 (2): 106–113. July 2004. doi:10.4161/rna.1.2.1066. PMID 17179747. 
  5. ↑ "Positive regulation of hepatic miR-122 expression by HNF4α". Journal of Hepatology 55 (3): 602–611. September 2011. doi:10.1016/j.jhep.2010.12.023. PMID 21241755. 
  6. ↑ "Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation". Genome Biology 5 (3): R13. 2004. doi:10.1186/gb-2004-5-3-r13. PMID 15003116. 
  7. ↑ "Integration of microRNA miR-122 in hepatic circadian gene expression". Genes & Development 23 (11): 1313–1326. June 2009. doi:10.1101/gad.1781009. PMID 19487572. 
  8. ↑ "Selective stabilization of mammalian microRNAs by 3' adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2". Genes & Development 23 (4): 433–438. February 2009. doi:10.1101/gad.1761509. PMID 19240131. 
  9. ↑ "Relief of microRNA-mediated translational repression in human cells subjected to stress". Cell 125 (6): 1111–1124. June 2006. doi:10.1016/j.cell.2006.04.031. PMID 16777601. 
  10. ↑ "Silencing of microRNAs in vivo with 'antagomirs'". Nature 438 (7068): 685–689. December 2005. doi:10.1038/nature04303. PMID 16258535. Bibcode: 2005Natur.438..685K. 
  11. ↑ "miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting". Cell Metabolism 3 (2): 87–98. February 2006. doi:10.1016/j.cmet.2006.01.005. PMID 16459310. 
  12. ↑ "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 Research 36 (4): 1153–1162. March 2008. doi:10.1093/nar/gkm1113. PMID 18158304. 
  13. ↑ "The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice". The Journal of Clinical Investigation 121 (4): 1386–1396. April 2011. doi:10.1172/JCI44883. PMID 21364282. 
  14. ↑ "LNA-mediated microRNA silencing in non-human primates". Nature 452 (7189): 896–899. April 2008. doi:10.1038/nature06783. PMID 18368051. Bibcode: 2008Natur.452..896E. 
  15. ↑ "Downregulation of miR-122 in the rodent and human hepatocellular carcinomas". Journal of Cellular Biochemistry 99 (3): 671–678. October 2006. doi:10.1002/jcb.20982. PMID 16924677. 
  16. ↑ "Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties". Oncogene 28 (40): 3526–3536. October 2009. doi:10.1038/onc.2009.211. PMID 19617899. 
  17. ↑ 17.0 17.1 "MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib". The Journal of Biological Chemistry 284 (46): 32015–32027. November 2009. doi:10.1074/jbc.M109.016774. PMID 19726678. 
  18. ↑ 18.0 18.1 "MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells". Cancer Research 69 (14): 5761–5767. July 2009. doi:10.1158/0008-5472.CAN-08-4797. PMID 19584283. 
  19. ↑ "MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma". Hepatology 49 (5): 1571–1582. May 2009. doi:10.1002/hep.22806. PMID 19296470. 
  20. ↑ "Hepatitis C virus and human miR-122: insights from the bench to the clinic". Current Opinion in Virology 7: 11–18. August 2014. doi:10.1016/j.coviro.2014.03.005. PMID 24721497. 
  21. ↑ 21.0 21.1 21.2 "MicroRNA as Type I Interferon-Regulated Transcripts and Modulators of the Innate Immune Response". Frontiers in Immunology 6: 334. 2015. doi:10.3389/fimmu.2015.00334. PMID 26217335. 
  22. ↑ 22.0 22.1 22.2 22.3 "HepG2 cells mount an effective antiviral interferon-lambda based innate immune response to hepatitis C virus infection". Hepatology 60 (4): 1170–1179. October 2014. doi:10.1002/hep.27227. PMID 24833036. 
  23. ↑ 23.0 23.1 "IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection". Hepatology 56 (6): 2060–2070. December 2012. doi:10.1002/hep.25897. PMID 22706965. 
  24. ↑ 24.0 24.1 "HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons". Gastroenterology 142 (4): 978–988. April 2012. doi:10.1053/j.gastro.2011.12.055. PMID 22248663. 
  25. ↑ 25.0 25.1 "HepG2 cells expressing microRNA miR-122 support the entire hepatitis C virus life cycle". Journal of Virology 85 (22): 12087–12092. November 2011. doi:10.1128/jvi.05843-11. PMID 21917968. 
  26. ↑ 26.0 26.1 26.2 "Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy". Nature Medicine 15 (1): 31–33. January 2009. doi:10.1038/nm.1902. PMID 19122656. 
  27. ↑ 27.0 27.1 27.2 "Modulation of miR‑122 expression affects the interferon response in human hepatoma cells". Molecular Medicine Reports 7 (2): 585–590. February 2013. doi:10.3892/mmr.2012.1233. PMID 23241652. 
  28. ↑ 28.0 28.1 28.2 "Inhibition of alpha interferon (IFN-α)-induced microRNA-122 negatively affects the anti-hepatitis B virus efficiency of IFN-α". Journal of Virology 87 (1): 137–147. January 2013. doi:10.1128/jvi.01710-12. PMID 23055569. 
  29. ↑ 29.0 29.1 "Down-regulation of suppressor of cytokine signaling 3 by miR-122 enhances interferon-mediated suppression of hepatitis B virus". Antiviral Research 118: 20–28. June 2015. doi:10.1016/j.antiviral.2015.03.001. PMID 25766860. 
  30. ↑ "MiR-122 directly inhibits human papillomavirus E6 gene and enhances interferon signaling through blocking suppressor of cytokine signaling 1 in SiHa cells". PLOS ONE 9 (9): e108410. 2014. doi:10.1371/journal.pone.0108410. PMID 25265013. Bibcode: 2014PLoSO...9j8410H. 
  31. ↑ 31.0 31.1 31.2 "MiR-122 modulates type I interferon expression through blocking suppressor of cytokine signaling 1". The International Journal of Biochemistry & Cell Biology 45 (4): 858–865. April 2013. doi:10.1016/j.biocel.2013.01.008. PMID 23348614. 
  32. ↑ "Hepatitis C virus represses the cellular antiviral response by upregulating the expression of signal transducer and activator of transcription 3 through sponging microRNA‑122". Molecular Medicine Reports 11 (3): 1733–1737. March 2015. doi:10.3892/mmr.2014.2897. PMID 25377467. 
  33. ↑ "Silencing of microRNA-122 enhances interferon-α signaling in the liver through regulating SOCS3 promoter methylation". Scientific Reports 2: 637. 2012. doi:10.1038/srep00637. PMID 22957141. Bibcode: 2012NatSR...2E.637Y. 
  34. ↑ "Interferon modulation of cellular microRNAs as an antiviral mechanism". Nature 449 (7164): 919–922. October 2007. doi:10.1038/nature06205. PMID 17943132. Bibcode: 2007Natur.449..919P. 
  35. ↑ "Transcriptional regulation of IFN-λ genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-κB complex". The Journal of Biological Chemistry 289 (8): 5310–5319. February 2014. doi:10.1074/jbc.m113.536102. PMID 24385435. 
  36. ↑ "IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System". PLOS ONE 10 (12): e0141655. 2015. doi:10.1371/journal.pone.0141655. PMID 26657215. Bibcode: 2015PLoSO..1041655A. 
  37. ↑ "Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA". Science 309 (5740): 1577–1581. September 2005. doi:10.1126/science.1113329. PMID 16141076. Bibcode: 2005Sci...309.1577J. 
  38. ↑ "Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome". Cell Host & Microbe 4 (1): 77–85. July 2008. doi:10.1016/j.chom.2008.05.013. PMID 18621012. 
  39. ↑ "Cellular cofactors affecting hepatitis C virus infection and replication". Proceedings of the National Academy of Sciences of the United States of America 104 (31): 12884–12889. July 2007. doi:10.1073/pnas.0704894104. PMID 17616579. Bibcode: 2007PNAS..10412884R. 
  40. ↑ "microRNA-122 stimulates translation of hepatitis C virus RNA". The EMBO Journal 27 (24): 3300–3310. December 2008. doi:10.1038/emboj.2008.244. PMID 19020517. 
  41. ↑ "Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122". Journal of Virology 84 (13): 6615–6625. July 2010. doi:10.1128/JVI.00417-10. PMID 20427538. 
  42. ↑ "Modulation of hepatitis C virus RNA abundance and the isoprenoid biosynthesis pathway by microRNA miR-122 involves distinct mechanisms". Journal of Virology 84 (1): 666–670. January 2010. doi:10.1128/JVI.01156-09. PMID 19846523. 
  43. ↑ "miR-122 does not modulate the elongation phase of hepatitis C virus RNA synthesis in isolated replicase complexes". Antiviral Research 88 (1): 119–123. October 2010. doi:10.1016/j.antiviral.2010.07.004. PMID 20637242. 
  44. ↑ "Human Ago2 is required for efficient microRNA 122 regulation of hepatitis C virus RNA accumulation and translation". Journal of Virology 85 (5): 2342–2350. March 2011. doi:10.1128/JVI.02046-10. PMID 21177824. 
  45. ↑ "Masking the 5' terminal nucleotides of the hepatitis C virus genome by an unconventional microRNA-target RNA complex". Proceedings of the National Academy of Sciences of the United States of America 108 (8): 3193–3198. February 2011. doi:10.1073/pnas.1012464108. PMID 21220300. Bibcode: 2011PNAS..108.3193M. 
  46. ↑ "A structured RNA motif locks Argonaute2:miR-122 onto the 5' end of the HCV genome". Nature Communications 12 (1): 6836. November 2021. doi:10.1038/s41467-021-27177-9. PMID 34824224. Bibcode: 2021NatCo..12.6836G. 
  47. ↑ "DDX6 (Rck/p54) is required for efficient hepatitis C virus replication but not for internal ribosome entry site-directed translation". Journal of Virology 84 (13): 6810–6824. July 2010. doi:10.1128/JVI.00397-10. PMID 20392846. 
  48. ↑ "IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C". Hepatology 52 (6): 1888–1896. December 2010. doi:10.1002/hep.23912. PMID 20931559. 
  49. ↑ "The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market". Pharmaceutical Research 34 (7): 1339–1363. July 2017. doi:10.1007/s11095-017-2134-2. PMID 28389707. 
  50. ↑ "Circulating microRNAs, potential biomarkers for drug-induced liver injury". Proceedings of the National Academy of Sciences of the United States of America 106 (11): 4402–4407. March 2009. doi:10.1073/pnas.0813371106. PMID 19246379. Bibcode: 2009PNAS..106.4402W. 
  51. ↑ "Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection". The American Journal of Gastroenterology 106 (9): 1663–1669. September 2011. doi:10.1038/ajg.2011.161. PMID 21606975. 
  52. ↑ "Hepatocyte-derived microRNAs as sensitive serum biomarkers of hepatocellular injury in Labrador retrievers". Veterinary Journal 211: 75–81. May 2016. doi:10.1016/j.tvjl.2016.01.010. PMID 27021912. 
  53. ↑ 53.0 53.1 "Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation". Liver Transplantation 18 (3): 290–297. March 2012. doi:10.1002/lt.22438. PMID 21932376. 
  54. ↑ Verhoeven, CJ, van der Laan, LJ, de Jonge, J, Metselaar, HJ (2017). Biomarkers to Monitor Graft Function Following Liver Transplantation. Biomarkers in Liver Disease. V. B. Patel and V. R. Preedy. Dordrecht, Springer Netherlands: ISBN:978-94-007-7675-3, page 193–220.
  55. ↑ "The release of microRNA-122 during liver preservation is associated with early allograft dysfunction and graft survival after transplantation". Liver Transplantation 23 (7): 946–956. July 2017. doi:10.1002/lt.24766. PMID 28388830. https://lirias.kuleuven.be/handle/123456789/581417. 
  56. ↑ "Clinical significance and potential of hepatic microRNA-122 expression in hepatitis C". Liver International 31 (4): 474–484. April 2011. doi:10.1111/j.1478-3231.2010.02433.x. PMID 21199296. 
  57. ↑ "Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122". Journal of Viral Hepatitis 20 (3): 158–166. March 2013. doi:10.1111/jvh.12001. PMID 23383654. 
  58. ↑ "Correlation between plasma miR-122 expression and liver injury induced by hepatectomy". The Journal of International Medical Research 42 (1): 77–84. February 2014. doi:10.1177/0300060513499093. PMID 24287929. 
  59. ↑ "Improving Accuracy of Urinary miRNA Quantification in Heparinized Patients Using Heparinase I Digestion". The Journal of Molecular Diagnostics 18 (6): 825–833. November 2016. doi:10.1016/j.jmoldx.2016.06.006. PMID 27598820. 
  60. ↑ "Corrigendum to "MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation" [J Hepatol 2013; 59:1231-1238]". Journal of Hepatology 67 (6): 1358. September 2017. doi:10.1016/j.jhep.2017.09.001. PMID 28964525. 

Further reading

External links



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