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Oncotarget. 2017 Nov 9;9(5):5517-5528. doi: 10.18632/oncotarget.22342. eCollection 2018 Jan 19.

Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC).

Author information

1
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
2
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3
Division of Oncology, Department Pathology, Stanford University School of Medicine, Stanford, CA, USA.
4
Regulus Therapeutics, San Diego, CA, USA.

Abstract

Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17 in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.

KEYWORDS:

HCC; MYC; lipid nanoparticle (LNP); liver cancer; miR

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