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. 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. The liver-specific expression of miR-122 is conserved in zebrafish. 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. 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. 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. 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. 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.
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. 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. 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. miR-122 inhibition in mice or primates does not result in any detectable liver toxicity.
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. 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. Several miR-122 target genes have been implicated in tumorigenesis, including ADAM10, IGF1R, CCNG1 and ADAM17.
Innate Immunity Recent studies demonstrated that miR-122 may directly regulate different aspects of the interferons (IFNs) signaling pathway to enhanced induction of anti-viral genes and inhibition of various virus. Moreover, miR-122 have been shown to target various genes, resulting in enhancement of IFN signaling and subsequent antiviral innate immunity. Interferons (IFNs, includes type I and III interferon) treatment leads to a significant reduction in the expression of the liver-specific miR-122. 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)).
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