Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver
Shu-hao Hsu, … , Joshua T. Mendell, Kalpana Ghoshal
Shu-hao Hsu, … , Joshua T. Mendell, Kalpana Ghoshal
Published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):2871-2883. https://doi.org/10.1172/JCI63539.
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Research Article

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

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 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.

Authors

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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Figure 1

Abnormal liver structure and TG metabolism in Mir122-LKO mice in early adult life.

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Abnormal liver structure and TG metabolism in Mir122-LKO mice in early a...
(A and B) Northern blot analysis of miRNA levels in liver. (C) Representative liver sections of 8-week-old control (floxed) and LKO mice after overnight fasting (n = 8–10 mice per genotype). Scale bars: top row, 200 μm; bottom row, 25 μm. (D) Oil red O– and PAS-stained liver sections from 8-week-old LKO mice after overnight fasting (n = 5 per genotype). Scale bars: top row, 100 μm; bottom row, 100 μm; insets, 25 μm. (E) Transmission electron micrographs of liver sections from 12-week-old LKO mice. Lipid droplets (L), ER, mitochondria (M), and nucleus (N) are labeled. Scale bars: top row, 2 μm; bottom row, 450 nm. (F) CK19 and A6 staining of bile duct and oval cells, respectively, in LKO livers (n = 3 mice per genotype). Scale bars: top row, 100 μm; inset, 5 μm; bottom row, 25 μm. (G) Hepatic TG and cholesterol levels in 10-week-old LKO mice. (H) De novo TG synthesis in liver as measured by 3H1-glycerol incorporation. (I) TG secretion as measured by monitoring serum TG levels after administration of Triton WR-1339. The results presented in G–I are mean ± SD. Statistical significance was calculated using a 2-tailed t test.