title: Anti-miR-21 Suppresses Hepatocellular Carcinoma Growth via Broad Transcriptional Network Deregulation.
abstract: Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options available to cancer patients. MicroRNA 21-5p (miR-21) has been shown to be upregulated in HCC, but the contribution of this oncomiR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miRNAs) and used them to interrogate dependency on miR-21 in a panel of liver cancer cell lines. Treatment with anti-miR-21, but not with a mismatch control anti-miRNA, resulted in significant derepression of direct targets of miR-21 and led to loss of viability in the majority of HCC cell lines tested. Robust induction of caspase activity, apoptosis, and necrosis was noted in anti-miR-21-treated HCC cells. Furthermore, ablation of miR-21 activity resulted in inhibition of HCC cell migration and suppression of clonogenic growth. To better understand the consequences of miR-21 suppression, global gene expression profiling was performed on anti-miR-21-treated liver cancer cells, which revealed striking enrichment in miR-21 target genes and deregulation of multiple growth-promoting pathways. Finally, in vivo dependency on miR-21 was observed in two separate HCC tumor xenograft models. In summary, these data establish a clear role for miR-21 in the maintenance of tumorigenic phenotype in HCC in vitro and in vivo.
  
  
  CONCLUSIONS
  miR-21 is important for the maintenance of the tumorigenic phenotype of HCC and represents a target for pharmacologic intervention.
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Wagenaar
authors.affiliation: Regulus Therapeutics, San Diego, California.
authors.forename: Sonya
authors.initials: S
authors.lastname: Zabludoff
authors.affiliation: Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Ahn
authors.affiliation: Regulus Therapeutics, San Diego, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Allerson
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Heike
authors.initials: H
authors.lastname: Arlt
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.affiliation: Regulus Therapeutics, San Diego, California.
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.affiliation: Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: Rajula
authors.initials: R
authors.lastname: Gaur
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Shih-Min A
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Deokhoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Sanofi BioInnovation, Nucleic Acid Therapeutics Platform, Frankfurt, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Metz-Weidmann
authors.affiliation: Regulus Therapeutics, San Diego, California.
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Jack
authors.initials: J
authors.lastname: Pollard
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Jason
authors.initials: J
authors.lastname: Reeves
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rocnik
authors.affiliation: Sanofi BioInnovation, Nucleic Acid Therapeutics Platform, Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Scheidler
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Chaomei
authors.initials: C
authors.lastname: Shi
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tolstykh
authors.affiliation: Genzyme R&D Center, Framingham, Massachusetts.
authors.forename: William
authors.initials: W
authors.lastname: Weber
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Winter
authors.affiliation: Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Qunyan
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts.
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Sanofi Oncology, Cambridge, MA Massachusetts. Dmitri.Wiederschain@sanofi.com.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects*; D064593:Heterografts; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense