Genome-Wide Profile of Pleural Mesothelioma versus Parietal and Visceral Pleura: The Emerging Gene Portrait of the Mesothelioma Phenotype

Malignant pleural mesothelioma is considered an almost incurable tumour with increasing incidence worldwide. It usually develops in the parietal pleura, from mesothelial lining or submesothelial cells, subsequently invading the visceral pleura. Chromosomal and genomic aberrations of mesothelioma are diverse and heterogenous. Genome-wide profiling of mesothelioma versus parietal and visceral normal pleural tissue could thus reveal novel genes and pathways explaining its aggressive phenotype.Well-characterised tissue from five mesothelioma patients and normal parietal and visceral pleural samples from six non-cancer patients were profiled by Affymetrix oligoarray of 38 500 genes. The lists of differentially expressed genes tested for overrepresentation in KEGG PATHWAYS (Kyoto Encyclopedia of Genes and Genomes) and GO (gene ontology) terms revealed large differences of expression between visceral and parietal pleura, and both tissues differed from mesothelioma. Cell growth and intrinsic resistance in tumour versus parietal pleura was reflected in highly overexpressed cell cycle, mitosis, replication, DNA repair and anti-apoptosis genes. Several genes of the “salvage pathway” that recycle nucleobases were overexpressed, among them TYMS, encoding thymidylate synthase, the main target of the antifolate drug pemetrexed that is active in mesothelioma. Circadian rhythm genes were expressed in favour of tumour growth. The local invasive, non-metastatic phenotype of mesothelioma, could partly be due to overexpression of the known metastasis suppressors NME1 and NME2. Down-regulation of several tumour suppressor genes could contribute to mesothelioma progression. Genes involved in cell communication were down-regulated, indicating that mesothelioma may shield itself from the immune system. Similarly, in non-cancer parietal versus visceral pleura signal transduction, soluble transporter and adhesion genes were down-regulated. This could represent a genetical platform of the parietal pleura propensity to develop mesothelioma.Genome-wide microarray approach using complex human tissue samples revealed novel expression patterns, reflecting some important features of mesothelioma biology that should be further explored

Cytotoxicity and global transcriptional responses induced by zinc oxide nanoparticles NM 110 in PMA-differentiated THP-1 cells

Despite a wide production and use of zinc oxide nanoparticles (ZnONP), their toxicological study is only of limited number and their impact at a molecular level is seldom addressed. Thus, we have used, as a model, zinc oxide nanoparticle NM110 (ZnO110NP) exposure to PMA-differentiated THP-1 macrophages. The cell viability was studied at the cellular level using WST-1, LDH and Alamar Blue® assays, as well as at the molecular level by transcriptomic analysis. Exposure of cells to ZnO110NP for 24 h decreased their viability in a dose-dependent manner with mean inhibitory concentrations (IC50) of 8.1 μg/mL. Transcriptomic study of cells exposed to two concentrations of ZnO110NP: IC50 and a quarter of it (IC50/4) for 4 h showed that the expressions of genes involved in metal metabolism are perturbed. In addition, expression of genes acting in transcription regulation and DNA binding, as well as clusters of genes related to protein synthesis and structure were altered. It has to be noted that the expressions of metallothioneins genes (MT1, MT2) and genes of heat-shock proteins genes (HSP) were strongly upregulated for both conditions. These genes might be used as an early marker of exposure to ZnONP. On the contrary, at IC50 exposure, modifications of gene expression involved in inflammation, apoptosis and mitochondrial suffering were noted indicating a less specific cellular response. Overall, this study brings a resource of transcriptional data for ZnONP toxicity for further mechanistic studies

Button battery induced cellular damage: a pathophysiological study

Button batteries (BB) are frequently swallowed and must be removed immediately as, if they remain in the esophagus, they can cause severe damage with fatal prognosis. To better understand the molecular mechanism of esophagus damage, we performed a study aimed to analyze heat production, pH variation, electrical work and metal release from BB incubated in cell culture media. Cytotoxicity and apoptosis induced in a human monocytes cell line (U937) was also investigated.Calculated transferred heat was around 244 J with a maximal increase of temperature of 7.26 K/g medium whose pH, reflecting medium electrolysis, was 12.2 after about 2 h incubation. Release of metals also occurred. Only 49.7 ± 1.9% of U937 monocytes remained viable after 90 min of incubation in DMEM containing BB. Those results suggest that BB discharge induce cytotoxicity and tissue injury probably due to multiple combinations of at least thermic, caustic and toxic phenomena. As maximal effects occurred in less than 2 h, they prompt for fast removal of battery from esophagus. Keywords: Button battery, Electrolysis, Calorimetry, Heat transfer, Metal ions, pH, Cytotoxicity, Apoptosi

Gene expression profile in monocyte during in vitro mineral fiber degradation

A human monocytes cell line, U-937, incubated in the presence of filtered medium from Escherichia coli culture (FS) has been previously reported to degrade man made mineral fiber and it has been indicated as a good paradigm of in vivo fiber biopersistence evaluation (manuscript accepted for publication). In the present paper, a study is reported aimed to define the molecular modification occurring in the U-937 monocytes during in vitro fiber degradation. The induction of gene expression was investigated in U-937 exposed to rock wool fibers (HDN) in the presence of FS by transcriptome analysis using 20 K DNA microarrays and quantitative RT-PCR. The over-expression of genes related to mobility and cellular adhesion, oxidative stress, immune system stimulation, enzymes, and ions transport protein systems were identified. Among them NCF1 gene, the gene encoding a subunit of NADPH oxidase, over-expression was detected. As the product of this gene allows the formation of superoxide anion that could lead to oxidative stress, HDN fibers were exposed to hydrogen peroxide. Fiber degradation similar to those observed upon incubation with U-937 in the presence of FS was obtained thus suggesting that reactive oxygen species production may be responsible for fiber degradation by U-937 monocytes