Targeting microRNAs: Towards a new tailored therapy for hepatocellular carcinoma
European Journal of Molecular & Clinical Medicine,
2015, Volume 2, Issue 2, Pages -
Abstract
Hepatocellular carcinoma (HCC) remains a significant unmet medical need with very limited therapeutic options available. Although microRNA-21 (miR-21) has been shown to be upregulated in HCC, its contribution as an onco-miR 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-miR-21) and used them to interrogate dependency on miR-21 in a panel of 20 commercially available HCC cell lines in vitro. Upon lipid-mediated transfection, anti-miR-21, but not its mismatched (MM) control, caused significant de-repression of known direct targets of miR-21, inhibited survival of a large subset of HCC cell lines. Sensitive HCC cell lines showed dose- and time-dependent induction of caspase 3/7 activity upon treatment with anti-miR-21. In contrast, non-responder HCC cell lines failed to significantly upregulate caspase activity and maintained viability in the presence of anti-miR compound. To better understand the consequences of miR-21 suppression in HCC,
Keywords:
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we carried out global gene expression profiling of anti miR 21 treated sensitive liver cancer cells. Striking enrichment in miR 21 targets was noted among upregulated transcripts. Key cellular processes affected by miR 21 inhibition including deregulation of metabolic pathways were identified by gene ontology analysis. In summary our data suggest that inhibition of miR 21 merits further investigation in the treatment of hepatocellular carcinoma
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