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

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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

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Hepatocellular Carcinoma
Anti-Inflammatory Agents
Liver
MicroRNAs
Hepacivirus
Physiologic Monitoring
Virus Replication
Hepatitis
Interleukin-6
Neoplasms
Carcinogenesis
Homeostasis
Cholesterol
Maintenance
Cytokines
Neoplasm Metastasis
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hsu, S. H., Wang, B., Kota, J., Yu, J., Costinean, S., Kutay, H., ... 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

Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. / Hsu, Shu Hao; Wang, Bo; Kota, Janaiah; Yu, Jianhua; Costinean, Stefan; Kutay, Huban; Yu, Lianbo; Bai, Shoumei; Perle, Krista La; Chivukula, Raghu R.; Mao, Hsiaoyin; Wei, Min; Clark, K. Reed; Mendell, Jerry R.; Caligiuri, Michael A.; Jacob, Samson T.; Mendell, Joshua T.; Ghoshal, Kalpana.

In: Journal of Clinical Investigation, Vol. 122, No. 8, 01.08.2012, p. 2871-2883.

Research output: Contribution to journalArticle

Hsu, SH, Wang, B, Kota, J, Yu, J, Costinean, S, Kutay, H, Yu, L, Bai, S, Perle, KL, Chivukula, RR, Mao, H, Wei, M, Clark, KR, Mendell, JR, Caligiuri, MA, Jacob, ST, Mendell, JT & Ghoshal, K 2012, 'Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver', Journal of Clinical Investigation, vol. 122, no. 8, pp. 2871-2883. https://doi.org/10.1172/JCI63539
Hsu, Shu Hao ; Wang, Bo ; Kota, Janaiah ; Yu, Jianhua ; Costinean, Stefan ; Kutay, Huban ; Yu, Lianbo ; Bai, Shoumei ; Perle, Krista La ; Chivukula, Raghu R. ; Mao, Hsiaoyin ; Wei, Min ; Clark, K. Reed ; Mendell, Jerry R. ; Caligiuri, Michael A. ; Jacob, Samson T. ; Mendell, Joshua T. ; Ghoshal, Kalpana. / Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 8. pp. 2871-2883.
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AU - Wei, Min

AU - Clark, K. Reed

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