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MiR-221 overexpression contributes to liver tumorigenesis.

ABSTRACT: MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.

SUBMITTER: Pineau P

PROVIDER: S-EPMC2806773 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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miR-221 overexpression contributes to liver tumorigenesis.

Pineau Pascal P Volinia Stefano S McJunkin Katherine K Marchio Agnès A Battiston Carlo C Terris Benoît B Mazzaferro Vincenzo V Lowe Scott W SW Croce Carlo M CM Dejean Anne A

Proceedings of the National Academy of Sciences of the United States of America 20091215 1

MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease p ...[more]

PMID: 20018759

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Project description:BACKGROUND & AIMS:Hepatic stellate cells (HSCs) have a role in liver fibrosis. Guanine nucleotide-binding ?-subunit 12 (G?12) converges signals from G-protein-coupled receptors whose ligand levels are elevated in the environment during liver fibrosis; however, information is lacking on the effect of G?12 on HSC trans-differentiation. This study investigated the expression of G?12 in HSCs and the molecular basis of the effects of its expression on liver fibrosis. METHODS:G?12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of G?12 in liver fibrosis was estimated using a toxicant injury mouse model with G?12 gene knockout and/or HSC-specific G?12 delivery using lentiviral vectors, in addition to primary HSCs and LX-2 cells using microRNA (miR) inhibitors, overexpression vectors, or adenoviruses. miR-16, G?12, and LC3 were also examined in samples from patients with fibrosis. RESULTS:G?12 was overexpressed in activated HSCs and fibrotic liver, and was colocalised with desmin. In a carbon tetrachloride-induced fibrosis mouse model, G?12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of G?12. Moreover, G?12 activation promoted autophagy accompanying c-Jun N-terminal kinase-dependent ATG12-5 conjugation. In addition, miR-16 was found to be a direct inhibitor of the de novo synthesis of G?12. Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than in their corresponding controls. Consistently, cirrhotic patient liver tissues showed G?12 and LC3 upregulation in desmin-positive areas. CONCLUSIONS:miR-16 dysregulation in HSCs results in G?12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation. This suggests that G?12 and its regulatory molecules could serve as targets for the amelioration of liver fibrosis. LAY SUMMARY:Guanine nucleotide-binding ?-subunit 12 (G?12) is upregulated in activated hepatic stellate cells (HSCs) as a consequence of the dysregulation of a specific microRNA that is abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by c-Jun N-terminal kinase-dependent ATG12-5 formation and the promotion of autophagy. We suggest that G?12 and its associated regulators could serve as new targets in HSCs for the treatment of liver fibrosis.

Dataset Information

MiR-221 overexpression contributes to liver tumorigenesis.

Publications

miR-221 overexpression contributes to liver tumorigenesis.

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