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

Oncotarget
Renumathy DhanasekaranDean W Felsher

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-17in 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.

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Citations

Oct 20, 2018·RNA Biology·Marjolein J G HooykaasRobert J Lebbink
Apr 2, 2019·Thyroid : Official Journal of the American Thyroid Association·Lauren Jin Suk JooStan B Sidhu
Feb 23, 2020·Molecular Human Reproduction·A Vashisht, G K Gahlay
Dec 17, 2020·International Journal of Molecular Sciences·Jessica McAnulty, Analisa DiFeo
Apr 4, 2021·International Journal of Molecular Sciences·Madalina Gabriela BarbuDragos Valentin Predescu
Nov 8, 2018·Gastroenterology·Renumathy DhanasekaranJessica Zucman-Rossi
Nov 4, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Maya S KrishnanRenumathy Dhanasekaran
Oct 21, 2020·Biomedical Journal·Po-Shuan HuangKwang-Huei Lin
Sep 12, 2021·Nature Reviews. Clinical Oncology·Renumathy DhanasekaranDean W Felsher
Oct 4, 2021·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Gordon Chun-Kau ChanCheuk-Chun Szeto

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Methods Mentioned

BETA
transgenic
transcription profiling
xenograft
xenografts
transfection
RNASeq
PCR

Software Mentioned

Sylarray
Sylamer
SPSS
Targetscan
Graphpad Prism
Osirix
Firehose

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