Protective effect of hepatocyte-enriched lncRNA-Mir122hg by promoting hepatocyte proliferation in acute liver injury
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Some long noncoding RNAs (lncRNAs), which harbor microRNAs in their gene sequence and are also known as microRNA host gene derived lncRNAs (lnc-MIRHGs), play a dominant role alongside miRNAs, or both perform biological functions synergistically or independently. However, only a small number of lnc-MIRHGs have been identified. Here, multiple liver injury datasets were analyzed to screen and identify the target lncRNA Mir122hg. Mir122hg was mainly enriched in liver tissues with human-mouse homology. In both CCl4-induced acute liver injury and Dgal/LPS-induced fulminant liver failure in mice, Mir122hg was sharply downregulated at the early stage, while a subsequent significant increase was only found in the CCl4 group with liver recovery. Overexpression and silencing assays confirmed that Mir122hg played a protective role in acute injury by promoting hepatocyte proliferation in vivo and in vitro. Consistent with the results of gene enrichment analysis, Mir122hg binding to C/EBPα affected its transcriptional repression, promoted gene transcription of downstream chemokines, Cxcl2, Cxcl3, and Cxcl5, and exerted pro-proliferative effects on hepatocytes through activation of the AKT/GSK-3β/p27 signaling pathway by CXC/CXCR2 complexes. This study identifies a novel lncRNA with protective effects in acute liver injury and demonstrates that the binding of Mir122hg-C/EBPα promotes hepatocyte proliferation via upregulation of CXC chemokine and activation of AKT signaling.
Abstract
Some long noncoding RNAs (lncRNAs), which harbor microRNAs in their gene sequence and are also known as microRNA host gene derived lncRNAs (lnc-MIRHGs), play a dominant role alongside miRNAs, or both perform biological functions synergistically or independently. However, only a small number of lnc-MIRHGs have been identified. Here, multiple liver injury datasets were analyzed to screen and identify the target lncRNA Mir122hg. Mir122hg was mainly enriched in liver tissues with human-mouse homology. In both CCl4-induced acute liver injury and Dgal/LPS-induced fulminant liver failure in mice, Mir122hg was sharply downregulated at the early stage, while a subsequent significant increase was only found in the CCl4 group with liver recovery. Overexpression and silencing assays confirmed that Mir122hg played a protective role in acute injury by promoting hepatocyte proliferation in vivo and in vitro. Consistent with the results of gene enrichment analysis, Mir122hg binding to C/EBPα affected its transcriptional repression, promoted gene transcription of downstream chemokines, Cxcl2, Cxcl3, and Cxcl5, and exerted pro-proliferative effects on hepatocytes through activation of the AKT/GSK-3β/p27 signaling pathway by CXC/CXCR2 complexes. This study identifies a novel lncRNA with protective effects in acute liver injury and demonstrates that the binding of Mir122hg-C/EBPα promotes hepatocyte proliferation via upregulation of CXC chemokine and activation of AKT signaling.
참고문헌 (35)
- Gao, Y., "CCL22 signaling contributes to sorafenib resistance in hepatitis B virus-associated hepatocellular carcinoma", Pharmacol. Res, 157, pp.104800~ (2020)
- Michalopoulos, G. K., "Liver regeneration: biological and pathological mechanisms and implications", Nat. Rev. Gastro. Hepat, 18, pp.40~55 (2021)
- Dong, V., "Pathophysiology of acute liver failure", Nutr. Clin. Pract, 35, pp.24~29 (2020)
- Ulitsky, I., "Evolution to the rescue : using comparative genomics to understand long non-coding RNAs", Nat. Rev. Genet, 17, pp.601~614 (2016)
- De Vincentis, A., "Long noncoding RNAs in nonalcoholic fatty liver disease and liver fibrosis : state-of-the-art and perspectives in diagnosis and treatment", Drug Discov. Today, 25, pp.1277~1286 (2020)
- Wang, H., "Long non-coding RNA(lncRNA)H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes", J. Cell. Mol. Med, 24, pp.1399~1412 (2020)
- Liu, Q. M., "Silencing lncRNA TUG1 Alleviates LPS-Induced Mouse Hepatocyte Inflammation by Targeting miR-140", TNF, 2020, pp.8, 616416~
- Qiang Wang, "Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation", Experimental and Molecular Medicine, 52, pp.1~12 (2020), 생화학분자생물학회[DOI]
- Wu, T., "Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure", Gut, 67, pp.2181~2191 (2018)
- Sun, Q., "One locus with two roles : microRNA-independent functions of microRNA-host-gene locus-encoded long noncoding RNAs", Wires RNA, 12, pp.e1625~ (2021)
- Dobin, A., "Mapping RNA-seq Reads with STAR", Curr. Protoc. Bioinfor, 51, pp.11.14.11~11.14.19 (2015)
- Zhang, K., "The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways", Nat. Commun, 8, pp.1~16 (2017)
- Bai, X., "Development of a DNA-templated peptide probe for photoaffinity labeling and enrichment of the histone modification reader", Proteins Angew. Chem. Int. Ed. Engl, 128, pp.8125~8129 (2016)
- R Development Core Team, "R: A language and environment for statistical computing" (2020), R Foundation for Statistical Computing
- Ezquerro, S., "Ghrelin reduces TNF-α–induced human hepatocyte apoptosis, autophagy, and pyroptosis : role in obesity-associated NAFLD", J. Clin. Endocrinol. Metab, 104, pp.21~37 (2019)
- Jing, Z. -T., "AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal", LPS-induced liver injury, 2019, pp.316, G387~G396
- Peng, W. C., "Inflammatory cytokine TNFα promotes the long-term expansion of primary hepatocytes in 3D culture", Cell, 175, pp.1607~1619.e1615 (2018)
- Ozaki, M., "Cellular and molecular mechanisms of liver regeneration : Proliferation, growth, death and protection of hepatocytes", Semin. Cell. Dev. Biol, 100, pp.62~73 (2020)
- Van Sweringen, H. L., "CXC chemokine signaling in the liver: impact on repair and regeneration", Hepatology, 54, pp.1445~1453 (2011)
- Veenstra, M., "Chemokine receptor CXCR2 : physiology regulator and neuroinflammation controller?", J. Neuroimmunol, 246, pp.1~9 (2012)
- Ren, R., "Aging exaggerates acute-on-chronic alcohol-induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1-C", EBPα-miRNA-223 axis, 2021, pp.75, 646~660
- Dhir, A., "Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs", Nat. Struct. Mol. Biol, 22, pp.319~327 (2015)
- Gebert, L. F., "Regulation of microRNA function in animals", Nat. Rev. Mol. Cell. Biol, 20, pp.21~37 (2019)
- Luna, J. M., "Argonaute CLIP defines a deregulated miR-122-bound transcriptome that correlates with patient survival in human liver cancer", Mol. Cell, 67, pp.400~410.e407 (2017)[DOI]
- Daniunaite, K., "Clinical significance of miRNA host gene promoter methylation in prostate cancer", Hum. Mol. Genet, 26, pp.2451~2461 (2017)
- Wang, S., "LncRNA MIR100HG promotes cell proliferation in triple-negative breast cancer through triplex formation with p27 loci", Cell. Death. Dis, 9, pp.1~11 (2018)
- Shih, J. W., "Long noncoding RNA LncHIFCAR", MIR31HG is a HIF-1α coactivator driving oral cancer progression, 2017, pp.8, 1~16
- Song, B., "Nano-designed carbon monoxide donor SMA", CORM2 exhibits protective effect against acetaminophen induced liver injury through macrophage reprograming and promoting liver regeneration, 2021, pp.331, 350~363
- Yang, W. T., "PRDM4 inhibits cell proliferation and tumorigenesis by inactivating the PI3K", AKT signaling pathway through targeting of PTEN in cervical carcinoma, 2021, pp.40, 3318~3330
- Lin, P. H., "Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation", J. Pineal Res, 68, pp.e12620~ (2020)
- Sun, Q., "Nuclear long noncoding RNAs : key regulators of gene expression", Trends Genet, 34, pp.142~157 (2018)
- Zhou, S. L., "Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma", Hepatology, 56, pp.2242~2254 (2012)
- Joshi, M., "Chemokine-mediated robust augmentation of liver engraftment : a novel approach", Stem. Cell. Transl. Med, 4, pp.21~30 (2015)
- Cassel, T. N., "C", EBP transcription factors in the lung epithelium, 2003, pp.285, L773~L781
- Sharma, A., "Lipopolysaccharide reverses hepatic stellate cell activation through modulation of cMyb, small mothers against decapentaplegic, and CCAAT", enhancer‐binding protein C, Hepatology, pp.2020, 72[DOI]