These authors contributed equally to this work.
MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma†
Article first published online: 23 DEC 2008
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 49, Issue 5, pages 1571–1582, May 2009
How to Cite
Tsai, W.-C., Hsu, P. W.-C., Lai, T.-C., Chau, G.-Y., Lin, C.-W., Chen, C.-M., Lin, C.-D., Liao, Y.-L., Wang, J.-L., Chau, Y.-P., Hsu, M.-T., Hsiao, M., Huang, H.-D. and Tsou, A.-P. (2009), MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology, 49: 1571–1582. doi: 10.1002/hep.22806
Potential conflict of interest: Nothing to report.
- Issue published online: 27 APR 2009
- Article first published online: 23 DEC 2008
- Accepted manuscript online: 23 DEC 2008 12:00AM EST
- Manuscript Accepted: 13 DEC 2008
- Manuscript Received: 12 AUG 2008
- 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
- Ministry of Education, Aim for the Top University Plan
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.)