miR-221 overexpression contributes to liver tumorigenesis

Pascal Pineau, Stefano Volinia, Katherine McJunkin, Agnès Marchio, Carlo Battiston, Benoît Terris, Vincenzo Mazzaferro, Scott W. Lowe, Carlo M. Croce, Anne Dejean

Research output: Contribution to journalArticle

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 upregulated 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.

Original languageEnglish
Pages (from-to)264-269
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number1
DOIs
Publication statusPublished - 2010

Fingerprint

MicroRNAs
Carcinogenesis
Hepatocellular Carcinoma
Liver
Liver Neoplasms
DNA Damage
Cyclin-Dependent Kinase Inhibitor p27
Regulator Genes
Growth
Oncogenes
Liver Cirrhosis
Disease Progression
Hepatocytes
Neoplasms
Stem Cells
Gene Expression
Cell Line

Keywords

  • AntagomiRs
  • DDIT4
  • Hepatocarcinogenesis
  • MicroRNA
  • Mouse model

ASJC Scopus subject areas

  • General

Cite this

miR-221 overexpression contributes to liver tumorigenesis. / Pineau, Pascal; Volinia, Stefano; McJunkin, Katherine; Marchio, Agnès; Battiston, Carlo; Terris, Benoît; Mazzaferro, Vincenzo; Lowe, Scott W.; Croce, Carlo M.; Dejean, Anne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 1, 2010, p. 264-269.

Research output: Contribution to journalArticle

Pineau, Pascal ; Volinia, Stefano ; McJunkin, Katherine ; Marchio, Agnès ; Battiston, Carlo ; Terris, Benoît ; Mazzaferro, Vincenzo ; Lowe, Scott W. ; Croce, Carlo M. ; Dejean, Anne. / miR-221 overexpression contributes to liver tumorigenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 1. pp. 264-269.
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AU - Lowe, Scott W.

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AU - Dejean, Anne

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AB - 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 upregulated 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.

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