Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of fun...

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Veröffentlicht in:The Journal of clinical investigation Jg. 122; H. 8; S. 2871 - 2883
Hauptverfasser: Hsu, Shu-hao, Wang, Bo, Kota, Janaiah, Yu, Jianhua, Costinean, Stefan, Kutay, Huban, Yu, Lianbo, Bai, Shoumei, La Perle, Krista, Chivukula, Raghu R., Mao, Hsiaoyin, Wei, Min, Clark, K. Reed, Mendell, Jerry R., Caligiuri, Michael A., Jacob, Samson T., Mendell, Joshua T., Ghoshal, Kalpana
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.08.2012
Schlagworte:
3' Untranslated Regions
Animals
Anti-inflammatory drugs
Base Sequence
Biomedical research
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - therapy
Cell Proliferation
Cell Survival - genetics
Cholesterol
Cytokines
Cytokines - biosynthesis
Fatty Liver - etiology
Fatty Liver - genetics
Fatty Liver - metabolism
Fatty Liver - pathology
Gene Expression
Genes
Genes, myc
Genes, Tumor Suppressor
Genotype & phenotype
Hepatitis C
Hepatitis C virus
Humans
Lipid Metabolism - genetics
Lipids - blood
Liver - immunology
Liver - metabolism
Liver - pathology
Liver cancer
Liver diseases
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - therapy
Liver Neoplasms, Experimental - etiology
Liver Neoplasms, Experimental - genetics
Liver Neoplasms, Experimental - metabolism
Metabolism
Metabolites
Metastasis
Mice
Mice, 129 Strain
Mice, Knockout
MicroRNA
MicroRNAs
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
MicroRNAs - metabolism
MicroRNAs - therapeutic use
Monocytes - immunology
Monocytes - pathology
Neutrophils - immunology
Neutrophils - pathology
Physiological aspects
RNA, Neoplasm - genetics
RNA, Neoplasm - metabolism
Tumor necrosis factor
Tumors
ISSN:0021-9738, 1558-8238, 1558-8238
Online-Zugang:Volltext
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Zusammenfassung:miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
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Authorship note: Shu-hao Hsu, Bo Wang, Janaiah Kota, Jianhua Yu, Stefan Costinean, Huban Kutay, Lianbo Yu, and Shoumei Bai contributed equally to this work.
ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI63539