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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Vydáno v:	The Journal of clinical investigation Ročník 122; číslo 8; s. 2871 - 2883
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 01.08.2012
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 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