MicroRNA-122, a tumor suppressor microRNA that regulates... : Hepatology (original) (raw)

Hepatobiliary Malignancies

MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma#

Tsai, Wei-Chih1†; Hsu, Paul Wei-Che5†; Lai, Tsung-Ching7†; Chau, Gar-Yang8; Lin, Ching-Wen1; Chen, Chun-Ming1; Lin, Chien-Der2; Liao, Yu-Lun1; Wang, Jui-Ling7; Chau, Yat-Pang3; Hsu, Ming-Ta4; Hsiao, Michael7†; Huang, Hsien-Da5,6†; Tsou, Ann-Ping1,7*† ‡

1 Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan (Republic of China [ROC])

2 Institute of Bioinformatics, National Yang-Ming University, Taipei, Taiwan (Republic of China [ROC])

3 Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan (Republic of China [ROC])

4 Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan (Republic of China [ROC])

5 Institute of Bioinformatics, National Chiao Tung University, Hsin-Chu, Taiwan (ROC)

6 Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan (ROC)

7 Genomics Research Center, Academic Sinica, Nankang, Taipei, Taiwan (ROC)

8 Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan (ROC)

* Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan, Republic of China

Email:[email protected]

Received August 12, 2008; accepted December 13, 2008.

Published online 18 March 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Science Council; Grant Numbers: NSC 96-3112-B-010-017 NSC 95-2752-B-010-002-PAE NSC 95-2311-B-009-004-MY3; Grant sponsor: Ministry of Education, Aim for the Top University Plan.

# Potential conflict of interest: Nothing to report.

† These authors contributed equally to this work.

‡ fax: (886)-2-28264092.

Additional Supporting Information may be found in the online version of this article.

Abstract

MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver-specific _microRNA_-122 (_miR_-122) is significantly down-regulated in liver cancers with intrahepatic metastastasis and negatively regulates tumorigenesis. Restoration of _miR_-122 in metastatic Mahlavu and SK-HEP-1 cells significantly reduced in vitro migration, invasion, and anchorage-independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple _miR_-122 candidate target genes from two independent expression microarray datasets. Thirty-two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling, and transcription. We further showed that one of the _miR_-122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of _miR_-122. Conclusion: Our study suggests that _miR_-122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of _miR_-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on _miR_-122 may prove to be beneficial for patients with hepatocellular carcinoma. (Hepatology 2009.)