Hepatocellular carcinoma (HCC) is one of the most common human malignancies with poor prognosis and urgent unmet medical need. Aberrant expression of multiple members of the microRNA-17 (miR-17) family are frequently observed in HCC and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacological inhibition of the miR-17 family inhibits HCC growth remains unknown. In the present study, we validated that the miR-17 family was up-regulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global de-repression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the de-regulated genes indicated that genes associated with TGF-β signaling pathway were highly enriched in Hep3B and HepG2 cells. A miR-17 family target gene signature was established and used to identify RL01-17(5), a lipid nanoparticle (LNP) encapsulating a potent anti-miR-17 family oligonucleotide. To address whether pharmacological modulation of the miR-17 family can inhibit HCC growth, RL01-17(5) was systemically administrated to orthotopic Hep3B xenografts. Suppression of Hep3B tumor growth in vivo was observed and tumor growth inhibition correlated with induction of miR-17 family target genes. Together, this study provides proof-of-concept for targeting the miR-17 family in HCC therapy.
- Received September 15, 2016.
- Revision received January 23, 2017.
- Accepted January 23, 2017.
- Copyright ©2017, American Association for Cancer Research.