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15357163mct160613-sup-171733_1_supp_3827453_djxwmd.pptx (157.61 kB)

Supplementary Figure 3S from Lipid Nanoparticle–Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

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posted on 2023-04-03, 14:43 authored by Xinqiang Huang, Jill Magnus, Vivek Kaimal, Priya Karmali, Jian Li, Marlena Walls, Rene Prudente, Eric Sung, Mehran Sorourian, Robin Lee, Scott Davis, Xia Yang, Heather Estrella, Edmund C. Lee, B. Nelson Chau, Adam Pavlicek, Sonya Zabludoff

Inhibition of miR-17 family by miR-17 TuD had no effect on caspase 3/7 activity. Caspase 3/7 activity was represented as relative activity compared to NC TuD expression cells.

Funding

Regulus Therapeutics, Inc.

History

ARTICLE ABSTRACT

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 miR-17 family are frequently observed in HCC, and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacologic inhibition of the miR-17 family inhibits HCC growth remains unknown. In this study, we validated that the miR-17 family was upregulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed the growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global derepression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the deregulated genes indicated that the genes associated with TGFβ 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 encapsulating a potent anti-miR-17 family oligonucleotide. To address whether pharmacologic 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. Mol Cancer Ther; 16(5); 905–13. ©2017 AACR.