Liver Cancer-Derived Hepatitis C Virus Core Proteins Shift TGF-Beta Responses from Tumor Suppression to Epithelial-Mesenchymal Transition

International audienceBACKGROUND: Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development

Determination of the Effects of Medium Composition on the Monochloramine Disinfection Kinetics of Nitrosomonas europaea by the Propidium Monoazide Quantitative PCR and Live/Dead BacLight Methods ▿

Various medium compositions (phosphate, 1 to 50 mM; ionic strength, 2.8 to 150 meq/liter) significantly affected Nitrosomonas europaea monochloramine disinfection kinetics, as determined by the Live/Dead BacLight (LD) and propidium monoazide quantitative PCR (PMA-qPCR) methods (lag coefficient, 37 to 490 [LD] and 91 to 490 [PMA-qPCR] mg·min/liter; Chick-Watson rate constant, 4.0 × 10−3 to 9.3 × 10−3 [LD] and 1.6 × 10−3 to 9.6 × 10−3 [PMA-qPCR] liter/mg·min). Two competing effects may account for the variation in disinfection kinetic parameters: (i) increasing kinetics (disinfection rate constant [k] increased, lag coefficient [b] decreased) with increasing phosphate concentration and (ii) decreasing kinetics (k decreased, b increased) with increasing ionic strength. The results support development of a standard medium for evaluating disinfection kinetics in drinking water

Biofilm Community Dynamics in Bench-Scale Annular Reactors Simulating Arrestment of Chloraminated Drinking Water Nitrification

Annular reactors (ARs) were used to study biofilm community succession and provide ecological insight during nitrification arrestment through simultaneously increasing monochloramine (NH₂Cl) and chlorine to nitrogen mass ratios, resulting in four operational periods (I–IV). Analysis of 16S rRNA-encoding gene sequence reads (454-pyrosequencing) examined viable and total biofilm communities and found total samples were representative of the underlying viable community. Bacterial community structure showed dynamic changes corresponding with AR operational parameters. Period I (complete nitrification and no NH₂Cl residual) was dominated by <i>Bradyrhizobium</i> (total cumulative distribution: 38%), while environmental <i>Legionella</i>-like phylotypes peaked (19%) during Period II (complete nitrification and minimal NH₂Cl residual). <i>Nitrospira moscoviensis</i> (nitrite-oxidizing bacteria) was detected in early periods (2%) but decreased to <0.02% in later periods, corresponding to nitrite accumulation. <i>Methylobacterium</i> (19%) and members of <i>Nitrosomonadaceae</i> (42%) dominated Period III (complete ammonia and partial nitrite oxidation and low NH₂Cl residual). An increase in <i>Afipia</i> (haloacetic acid-degrading bacteria) relative abundance (<2% to 42%) occurred during Period IV (minimal nitrification and moderate to high NH₂Cl residual). Microbial community and operational data provided no evidence of taxa-time relationship, but rapid community transitions indicated that the system had experienced ecological regime shifts to alternative stable states