Published online before print August 7, 2008

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(American Journal of Pathology. 2008;173:856-864.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080096

Elevated Expression of the miR-17–92 Polycistron and miR-21 in Hepadnavirus-Associated Hepatocellular Carcinoma Contributes to the Malignant Phenotype

Erin Connolly^*, Margherita Melegari^*, Pablo Landgraf, Tatyana Tchaikovskaya^*, Bud C. Tennant, Betty L. Slagle, Leslie E. Rogler^*, Mihaela Zavolan^¶, Thomas Tuschl and Charles E. Rogler^*

From the Marion Bessin Liver Research Center,^* Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; Laboratory of RNA Biology, Rockefeller University, New York, NY; Department of Animal Science, Cornell University College of Veterinary Medicine, Ithaca, NY; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas;^¶ Biozentrum, University of Basel, Switzerland and Swiss Institute of Bioinformatics, Lausanne, Switzerland

Alterations in microRNA (miRNA) expression in both human and animal models have been linked to many forms of cancer. Such miRNAs, which act directly as repressors of gene expression, have been found to frequently reside in fragile sites and genomic regions associated with cancer. This study describes a miRNA signature for human primary hepatitis B virus-positive human hepatocellular carcinoma. Moreover, two known oncomiRs—miRNAs with known roles in cancer—the miR-17–92 polycistron and miR-21, exhibited increased expression in 100% of primary human and woodchuck hepatocellular carcinomas surveyed. To determine the importance of these miRNAs in tumorigenesis, an in vitro antisense oligonucleotide knockdown model was evaluated for its ability to reverse the malignant phenotype. Both in human and woodchuck HCC cell lines, separate treatments with antisense oligonucleotides specific for either the miR-17–92 polycistron (all six members) or miR-21 caused a 50% reduction in both hepatocyte proliferation and anchorage-independent growth. The combination of assays presented here supports a role for these miRNAs in the maintenance of the malignant transformation of hepatocytes.