These two miRNAs, together with the two most up-regulated miRNAs, miR-96 and miR-182, require further study for understanding their relevance in HCC. Down-regulated miRNAs are of interest because they can act as tumor suppressors.39 Cellular miRNAs can also act as oncogenes,47 and their up-regulation in cancer will cause down-regulation of their tumor-suppressive targets.

In general, these miRNAs are potentially relevant for HCC therapy: tumor suppressor miRNAs can be introduced back in a cancer PI3K inhibitor cell, thereby repressing tumorigenesis, and oncogenic miRNAs can be inhibited by using synthetic miRNA antagonists or virally-delivered sponge-like sequences.48, 49 This brings exciting possibilities for the use of miRNAs as therapeutics. In the current study we experimentally verified 13 predicted miRNAs targets in five ABC genes using luciferase reporter assays. We were able to prove that the miRNA effect was sequence-specific by mutating the targets in the reporters and by cotransfecting miRNAs not having targets in ABC genes (data not shown). Except for ABCC4, our mutational analysis revealed some new miRNA targets in ABC genes. Strikingly, we were able to show that for several miRNA-ABC pairs, a very high proportion of the

analyzed tumors have an increased ABC gene expression level together with a reduced level of miRNA. Thus far the only evidence selleck chemical of miRNA-mediated regulation of ABC gene expression in HCC has been provided by Furuta et al.,27 who showed that miR-203 regulates the expression of ABCE1, which is involved in translation initiation, but has not been linked to multidrug resistance. With this perspective, we are currently working on in vitro validation of the miRNA-mediated regulation of endogenous ABC gene expression with a special focus on the ABCC subfamily. Future research will concentrate on delivery of these miRNAs as gene therapy, either in miRNA-replacement therapy for HCC

or as a novel indirect strategy to induce down-regulation of ABC transporters instead of direct short hairpin RNA (shRNA)- or artificial miRNA-mediated 3-mercaptopyruvate sulfurtransferase gene therapy approaches.50 The focus should be on ABCB6, ABCC1, ABCC4, ABCC5, ABCC10, and ABCC12 as these genes were up-regulated in more than 50% of the patients. The authors thank Françoise Degos, Bruno Clément, Bruno Turlin, and the Centre de Ressources Biologiques Foie (France) for providing clinical samples and data, and Cees B.M. Oudejans (Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands) for kindly providing access to the ABI 7900HT. Additional Supporting Information may be found in the online version of this article. “
“Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in human immunodeficiency virus (HIV) infection therapy. It has been associated with hepatotoxic effects and alterations in lipid and body fat composition.