Lipid Nanoparticle-Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth.
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 growthin vivowas 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.
Regulus Therapeutics Inc., San Diego, California. apavlicek@regulusrx.com xinqianghuang@yahoo.com.
Xinqiang
X
Huang
Regulus Therapeutics Inc., San Diego, California.
Jill
J
Magnus
Regulus Therapeutics Inc., San Diego, California.
Vivek
V
Kaimal
Regulus Therapeutics Inc., San Diego, California.
Priya
P
Karmali
Regulus Therapeutics Inc., San Diego, California.
Jian
J
Li
Regulus Therapeutics Inc., San Diego, California.
Marlena
M
Walls
Regulus Therapeutics Inc., San Diego, California.
Rene
R
Prudente
Regulus Therapeutics Inc., San Diego, California.
Eric
E
Sung
Regulus Therapeutics Inc., San Diego, California.
Mehran
M
Sorourian
Regulus Therapeutics Inc., San Diego, California.
Robin
R
Lee
Regulus Therapeutics Inc., San Diego, California.
Scott
S
Davis
Regulus Therapeutics Inc., San Diego, California.
Xia
X
Yang
Regulus Therapeutics Inc., San Diego, California.
Heather
H
Estrella
Regulus Therapeutics Inc., San Diego, California.
Edmund C
EC
Lee
Regulus Therapeutics Inc., San Diego, California.
B Nelson
BN
Chau
Regulus Therapeutics Inc., San Diego, California. apavlicek@regulusrx.com xinqianghuang@yahoo.com.
Adam
A
Pavlicek
Regulus Therapeutics Inc., San Diego, California.
Sonya
S
Zabludoff
D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage* / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000070416:Antagomirs; D008055:Lipids; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides