BioProject

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Like in many cancers, tumor heterogeneity in HCC hampers the development of personalized therapies. Integrative genomics contributed to characterize HCC subtypes by identifying specific genetic alterations and molecular signatures, leading to targeted drug candidates. However, no consensus was achieved for genes and pathways recurrently altered in HCC. Here, a meta-analysis of 15 independent HCC datasets identifies a comprehensive signature consisting of 935 genes commonly deregulated in HCC as compared to the surrounding non-tumor tissue (P<0.01). The 935-gene HCC signature covers well-established cancer hallmarks (e.g. proliferation, metabolic reprogramming, microenvironment remodeling) together with specific hallmarks associated with protein turnover and epigenetics. Accordingly, the 935-gene HCC signature highlights relevant drugs for systemic therapies, including including two histone deacetylase (HDAC) inhibitors (trichostatin A and vorinostat), PI3K inhibitor LY294002, mTOR inhibitor sirolimus (also known as rapamycin), alpha-estradiol and resveratrol. The impact of these drugs as compared to sorafenib that is currently used for the treatment of advanced HCC was evaluated on the viability of 6 HCC-derived cell lines. We concluded that combined therapies targeting common and subtype-specific cancer networks may represent a relevant strategy to efficiently treat liver cancer. Overall design: SNU-387 (ATCC® CRL-2237™, grade IV/V) and HepG2/C3A (ATCC® CRL-10741™) were grown in a RPMI-1640 medium supplemented with 100U/ml penicillin, 100μg/ml streptomycin and 10% fetal bovine serum. Cultures were performed at 37°C in a 5% CO2 atmosphere. Resveratrol, sorafenib and vorinostat were purchased from Santa Cruz Biotechnology (Heidelberg, Germany). All molecules were solubilized in a dimethyl sulfoxide (DMSO) solution. For the microarray experiments the concentrations were optimized to induce 50% cell mortality after a 72h drug exposure, in order to allow the extraction of nucleic acids from the remaining viable cells. Experiments were performed in monoplicates.