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

Shu Hao Hsu, Bo Wang, Janaiah Kota, Jianhua Yu, Stefan Costinean, Huban Kutay, Lianbo Yu, Shoumei Bai, Krista La Perle, Raghu R. Chivukula, Hsiaoyin Mao, Min Wei, K. Reed Clark, Jerry R. Mendell, Michael A. Caligiuri, Samson T. Jacob, Joshua T. Mendell, Kalpana Ghoshal

Research output: Contribution to journalArticle

478 Scopus citations

Abstract

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 protumorigenic 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.

Original languageEnglish (US)
Pages (from-to)2871-2883
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number8
DOIs
StatePublished - Aug 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Hsu, S. H., Wang, B., Kota, J., Yu, J., Costinean, S., Kutay, H., Yu, L., Bai, S., Perle, K. L., Chivukula, R. R., Mao, H., Wei, M., Clark, K. R., Mendell, J. R., Caligiuri, M. A., Jacob, S. T., Mendell, J. T., & Ghoshal, K. (2012). Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. Journal of Clinical Investigation, 122(8), 2871-2883. https://doi.org/10.1172/JCI63539