Authors: Melchiorre Cervello, Dimcho Bachvarov, Nadia Lampiasi, Antonella Cusimano, Antonina Azzolina, James A. McCubrey and Giuseppe Montalto

Melchiorre Cervello

Corresponding author: cervello@ibim.cnr.it
Institute of Biomedicine and Molecular Immunology “Alberto Monroy”; National Research Council (CNR); Palermo, Italy
These authors contributed equally to this work.

Dimcho Bachvarov

Corresponding author: dimtcho.batchvarov@crhdq.ulaval.ca
Cancer Research Centre; Hôpital L’Hotel-Dieu de Québec; Centre Hospitalier Universitaire de Québec; Québec, QC Canada; Department of Molecular Medicine; Faculty of Medicine; Laval University; Québec, QC Canada
These authors contributed equally to this work.

Nadia Lampiasi

Institute of Biomedicine and Molecular Immunology “Alberto Monroy”; National Research Council (CNR); Palermo, Italy

Antonella Cusimano

Institute of Biomedicine and Molecular Immunology “Alberto Monroy”; National Research Council (CNR); Palermo, Italy

Antonina Azzolina

Institute of Biomedicine and Molecular Immunology “Alberto Monroy”; National Research Council (CNR); Palermo, Italy

James A. McCubrey

Department of Microbiology and Immunology; Brody School of Medicine at East Carolina University; Greenville, NC USA

Giuseppe Montalto

Institute of Biomedicine and Molecular Immunology “Alberto Monroy”; National Research Council (CNR); Palermo, Italy; Department of Internal Medicine and Specialties; University of Palermo; Palermo, Italy

Abstract:
Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced hepatocellular carcinoma (HCC). However, as the clinical application of sorafenib evolves, there is increasing interest in defining the mechanisms underlying its anti-tumor activity. Considering that this specific inhibitor could target unexpected molecules depending on the biologic context, a precise understanding of its mechanism of action could be critical to maximize its treatment efficacy, while minimizing adverse effects. Two human HCC cell lines (HepG2 and Huh7), carrying different biological and genetic characteristics, were used in this study to examine the intracellular events leading to sorafenib-induced HCC cell-growth inhibition. Sorafenib inhibited cell growth in both cell lines in a dose- and time-dependent manner and significantly altered expression levels of 826 and 2011 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in angiogenesis, apoptosis, transcription regulation, signal transduction, protein biosynthesis and modification were predominantly upregulated, while genes implicated in cell cycle control, DNA replication recombination and repair, cell adhesion, metabolism and transport were mainly downregulated upon treatment. However, each sorafenib-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by western blotting. Many novel genes emerged from our transcriptomics analysis that had not previously been reported to be effected by sorafenib. Further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.

Received: April 24, 2012; Accepted: June 20, 2012

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