- Email: [email protected]
Cell-specific functions of miRNA in the liver
Accepted Manuscript Hepatology Snapshot Cell-specific functions of miRNA in the liver Christoph Roderburg, Christian Trautwein PII: DOI: Reference:
S0168-8278(16)30542-6 http://dx.doi.org/10.1016/j.jhep.2016.09.015 JHEPAT 6271
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
30 August 2016 26 September 2016 26 September 2016
Please cite this article as: Roderburg, C., Trautwein, C., Cell-specific functions of miRNA in the liver, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.09.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Snapshot
Cell-specific functions of miRNA in the liver
Christoph Roderburg* and Christian Trautwein
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen; Germany
Keywords: miRNA, microRNA, biomarker, liver, fibrosis, hepatocellular carcinoma Word-count: 584 words
*Address correspondence to: Christoph Roderburg, MD; Department of Medicine III, University Hospital RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany; Phone: +49-(0)241-80-80866; E-mail: [email protected]
1
Main text Background: miRNAs play essential roles in virtually all cellular and biological processes including liver development, differentiation and homeostasis [1, 2]. Altered expression levels of miRNAs were observed in patients with liver diseases e.g. liver steatosis, cirrhosis and hepatocellular carcinoma [1, 3]. Expression pattern of miRNAs are organ- and tissue-specific. In the liver, miRNAs are not homogeneously distributed but are selectively expressed and regulated in distinct hepatic cell types. For certain miRNAs, opposite regulation were described between the different liver cell compartments. As an example, expression of miR-29, one of the best studied miRNAs in liver diseases, was found to be down-regulated in hepatic stellate cells (HSC) during hepatofibrogenesis, while its expression was up-regulated in hepatocytes and cholangiocytes during experimental biliary atresia [4, 5], supporting the concept of cell-specific functions of miRNAs in liver (patho-)physiology.
Cell-specific functions of miRNAs in the liver Parenchymal hepatocytes are the main contributor of liver function [6]. miR-122 is selectively expressed in hepatocytes and contributes about 75% of the hepatic miRNome. miR-122 plays critical roles in liver homeostasis and metabolism. Silencing of miR-122 has been associated with steatohepatitis, fibrosis and HCC [7, 8]. A liver-specific knockout for miR-122 develops HCC by modulating expression of CyclinG1, ADAM10, IGF1R, SRF and Wnt1. Finally, presence of miR-122 was shown to be crucial for the replication of hepatitis C virus (HCV) and sequestration of miRNA-122 by the viral genome was suggested to contribute to the pathogenesis of HCV [9]. Besides miR-122, hepatocyte-specific functions were described for miR-155
2
in the context of alcoholic liver disease and for miR-192 in acute liver injury and HCV mediated liver fibrogenesis. Among
the
non-parenchymal
cells,
HSCs
produce
and
accumulate
extracellular matrix (ECM) proteins during liver fibrosis. miRNAs affect different steps of fibrogenesis including HSC activation, proliferation, migration, and ECM deposition. Most prominently, miR-29 was identified as an antifibrotic miRNA directly involved in HSC-activation. Similar to miR-29, members of the miR-17-92 cluster (including miR-19b) were significantly down-regulated in activated HSCs. miR-19b represses expression of TGFßRII, thereby blunting the activation of HSC. Next to these antifibrotic miRNAs, several profibrotic miRNAs are up-regulated during fibrogenesis: elevated expression of miR-21 enhances HSC-activation and EMT by activating the PTEN/Akt-signaling pathway. Moreover, TGF-ß induced up-regulation of miR-199s and miR-200 indirectly promotes liver fibrosis by increasing the expression of profibrotic genes (e.g. collagens, MMPs). Additional miRNAs dergulated in activated HSCs are listed in figure 1. In contrast to hepatocytes and HSC, data on specific functions of miRNAs in LSEC, Kupffer cells and cholangiocytes are scarce. It was suggested that miR-155 is up-regulated in alcohol-exposed RAW 264.7 macrophages, as well as in Kupffer cells from alcohol fed mice [9,10], inducing a pro-inflammatory environment that ultimately lead to steatosis, hepatitis and fibrosis. For
some
miRNAs
cell-type
specific
changes
were
suggested
by
corresponding alterations in serum concentrations. Up-regulation of miR-571 in hepatocytes and HSC was accompanied by elevated serum levels of this miRNA correlating with the stage of liver fibrosis in patients, while lower serum levels of miR652 correlated with a down-regulation of this miRNA in monocytes and reflected the
3
degree of liver inflammation [10]. Thus, circulating miRNAs were proposed as easily accessible biomarkers for diagnosis and monitoring of liver diseases [11, 12].
Outlook and discussion: Based on the obvious relevance in pathophysiology of liver diseases, a therapeutic use of miRNAs was proposed by many authors. Manipulation of miRNA expression represent an optimal approach for conditions in which ‘fine-tuning’ of whole gene expression networks seems more appropriate to restore homeostasis than inhibiting expression of single genes. Advances in gene-delivery systems will allow cell-specific targeting of miRNA expression and to selectively manipulate distinct aspects of the pathophysiology of liver diseases. Clinical investigations exploring miRNA-based therapeutic and diagnostic applications in liver diseases are ongoing. In a recent proof-of-principle trial, miravirsen (an LNA based miR-122-inhibitor) demonstrated efficacy in a phase 2a-trial on patients infected with HCV [13].
4
Acknowledgements The authors would like to express their gratitude to Dr. Sanchari Roy, Prof. Tom Luedde and Michaela Roderburg-Goor for helpful discussions.
Financial support This work was supported by the German Research Foundation (DFG RO 4317/4-1, TR 285/10-1) and by a START grant of the medical department of the RWTH Aachen. The funding bodies had no role in the design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Competing interests The authors declare that they have no competing interests.
5
References [1] Szabo G, Bala S. MicroRNAs in liver disease. Nature reviews Gastroenterology & hepatology 2013;10:542-552. [2] Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annual review of pathology 2014;9:287-314. [3] Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nature reviews Gastroenterology & hepatology 2015;12:387-400. [4] Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011;53:209-218. [5] Hand NJ, Horner AM, Master ZR, Boateng LA, LeGuen C, Uvaydova M, et al. MicroRNA profiling identifies miR-29 as a regulator of disease-associated pathways in experimental biliary atresia. Journal of pediatric gastroenterology and nutrition 2012;54:186192. [6] Zhou Z, Xu MJ, Gao B. Hepatocytes: a key cell type for innate immunity. Cellular & molecular immunology 2016;13:301-315. [7] Thakral S, Ghoshal K. miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir. Current gene therapy 2015;15:142-150. [8] Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122--a key factor and therapeutic target in liver disease. Journal of hepatology 2015;62:448-457. [9] Luna JM, Scheel TK, Danino T, Shaw KS, Mele A, Fak JJ, et al. Hepatitis C virus RNA functionally sequesters miR-122. Cell 2015;160:1099-1110. [10] Roderburg C, Mollnow T, Bongaerts B, Elfimova N, Vargas Cardenas D, Berger K, et al. Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis. PloS one 2012;7:e32999. [11] Yin CQ, Yuan CH, Qu Z, Guan Q, Chen H, Wang FB. Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers. Disease markers 2016;2016:1427849. [12] Steer CJ, Subramanian S. Circulating microRNAs as biomarkers: a new frontier in diagnostics. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2012;18:265-269. [13] Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. The New England journal of medicine 2013;368:1685-1694.
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S0168-8278(16)30542-6 http://dx.doi.org/10.1016/j.jhep.2016.09.015 JHEPAT 6271
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
30 August 2016 26 September 2016 26 September 2016
Please cite this article as: Roderburg, C., Trautwein, C., Cell-specific functions of miRNA in the liver, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.09.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Snapshot
Cell-specific functions of miRNA in the liver
Christoph Roderburg* and Christian Trautwein
Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen; Germany
Keywords: miRNA, microRNA, biomarker, liver, fibrosis, hepatocellular carcinoma Word-count: 584 words
*Address correspondence to: Christoph Roderburg, MD; Department of Medicine III, University Hospital RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany; Phone: +49-(0)241-80-80866; E-mail: [email protected]
1
Main text Background: miRNAs play essential roles in virtually all cellular and biological processes including liver development, differentiation and homeostasis [1, 2]. Altered expression levels of miRNAs were observed in patients with liver diseases e.g. liver steatosis, cirrhosis and hepatocellular carcinoma [1, 3]. Expression pattern of miRNAs are organ- and tissue-specific. In the liver, miRNAs are not homogeneously distributed but are selectively expressed and regulated in distinct hepatic cell types. For certain miRNAs, opposite regulation were described between the different liver cell compartments. As an example, expression of miR-29, one of the best studied miRNAs in liver diseases, was found to be down-regulated in hepatic stellate cells (HSC) during hepatofibrogenesis, while its expression was up-regulated in hepatocytes and cholangiocytes during experimental biliary atresia [4, 5], supporting the concept of cell-specific functions of miRNAs in liver (patho-)physiology.
Cell-specific functions of miRNAs in the liver Parenchymal hepatocytes are the main contributor of liver function [6]. miR-122 is selectively expressed in hepatocytes and contributes about 75% of the hepatic miRNome. miR-122 plays critical roles in liver homeostasis and metabolism. Silencing of miR-122 has been associated with steatohepatitis, fibrosis and HCC [7, 8]. A liver-specific knockout for miR-122 develops HCC by modulating expression of CyclinG1, ADAM10, IGF1R, SRF and Wnt1. Finally, presence of miR-122 was shown to be crucial for the replication of hepatitis C virus (HCV) and sequestration of miRNA-122 by the viral genome was suggested to contribute to the pathogenesis of HCV [9]. Besides miR-122, hepatocyte-specific functions were described for miR-155
2
in the context of alcoholic liver disease and for miR-192 in acute liver injury and HCV mediated liver fibrogenesis. Among
the
non-parenchymal
cells,
HSCs
produce
and
accumulate
extracellular matrix (ECM) proteins during liver fibrosis. miRNAs affect different steps of fibrogenesis including HSC activation, proliferation, migration, and ECM deposition. Most prominently, miR-29 was identified as an antifibrotic miRNA directly involved in HSC-activation. Similar to miR-29, members of the miR-17-92 cluster (including miR-19b) were significantly down-regulated in activated HSCs. miR-19b represses expression of TGFßRII, thereby blunting the activation of HSC. Next to these antifibrotic miRNAs, several profibrotic miRNAs are up-regulated during fibrogenesis: elevated expression of miR-21 enhances HSC-activation and EMT by activating the PTEN/Akt-signaling pathway. Moreover, TGF-ß induced up-regulation of miR-199s and miR-200 indirectly promotes liver fibrosis by increasing the expression of profibrotic genes (e.g. collagens, MMPs). Additional miRNAs dergulated in activated HSCs are listed in figure 1. In contrast to hepatocytes and HSC, data on specific functions of miRNAs in LSEC, Kupffer cells and cholangiocytes are scarce. It was suggested that miR-155 is up-regulated in alcohol-exposed RAW 264.7 macrophages, as well as in Kupffer cells from alcohol fed mice [9,10], inducing a pro-inflammatory environment that ultimately lead to steatosis, hepatitis and fibrosis. For
some
miRNAs
cell-type
specific
changes
were
suggested
by
corresponding alterations in serum concentrations. Up-regulation of miR-571 in hepatocytes and HSC was accompanied by elevated serum levels of this miRNA correlating with the stage of liver fibrosis in patients, while lower serum levels of miR652 correlated with a down-regulation of this miRNA in monocytes and reflected the
3
degree of liver inflammation [10]. Thus, circulating miRNAs were proposed as easily accessible biomarkers for diagnosis and monitoring of liver diseases [11, 12].
Outlook and discussion: Based on the obvious relevance in pathophysiology of liver diseases, a therapeutic use of miRNAs was proposed by many authors. Manipulation of miRNA expression represent an optimal approach for conditions in which ‘fine-tuning’ of whole gene expression networks seems more appropriate to restore homeostasis than inhibiting expression of single genes. Advances in gene-delivery systems will allow cell-specific targeting of miRNA expression and to selectively manipulate distinct aspects of the pathophysiology of liver diseases. Clinical investigations exploring miRNA-based therapeutic and diagnostic applications in liver diseases are ongoing. In a recent proof-of-principle trial, miravirsen (an LNA based miR-122-inhibitor) demonstrated efficacy in a phase 2a-trial on patients infected with HCV [13].
4
Acknowledgements The authors would like to express their gratitude to Dr. Sanchari Roy, Prof. Tom Luedde and Michaela Roderburg-Goor for helpful discussions.
Financial support This work was supported by the German Research Foundation (DFG RO 4317/4-1, TR 285/10-1) and by a START grant of the medical department of the RWTH Aachen. The funding bodies had no role in the design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
Competing interests The authors declare that they have no competing interests.
5
References [1] Szabo G, Bala S. MicroRNAs in liver disease. Nature reviews Gastroenterology & hepatology 2013;10:542-552. [2] Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annual review of pathology 2014;9:287-314. [3] Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nature reviews Gastroenterology & hepatology 2015;12:387-400. [4] Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011;53:209-218. [5] Hand NJ, Horner AM, Master ZR, Boateng LA, LeGuen C, Uvaydova M, et al. MicroRNA profiling identifies miR-29 as a regulator of disease-associated pathways in experimental biliary atresia. Journal of pediatric gastroenterology and nutrition 2012;54:186192. [6] Zhou Z, Xu MJ, Gao B. Hepatocytes: a key cell type for innate immunity. Cellular & molecular immunology 2016;13:301-315. [7] Thakral S, Ghoshal K. miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir. Current gene therapy 2015;15:142-150. [8] Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122--a key factor and therapeutic target in liver disease. Journal of hepatology 2015;62:448-457. [9] Luna JM, Scheel TK, Danino T, Shaw KS, Mele A, Fak JJ, et al. Hepatitis C virus RNA functionally sequesters miR-122. Cell 2015;160:1099-1110. [10] Roderburg C, Mollnow T, Bongaerts B, Elfimova N, Vargas Cardenas D, Berger K, et al. Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis. PloS one 2012;7:e32999. [11] Yin CQ, Yuan CH, Qu Z, Guan Q, Chen H, Wang FB. Liquid Biopsy of Hepatocellular Carcinoma: Circulating Tumor-Derived Biomarkers. Disease markers 2016;2016:1427849. [12] Steer CJ, Subramanian S. Circulating microRNAs as biomarkers: a new frontier in diagnostics. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2012;18:265-269. [13] Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. The New England journal of medicine 2013;368:1685-1694.
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