Induction of Bcl-2 Expression by Hepatitis B Virus Pre-S2 Mutant Large Surface Protein Resistance to 5-Fluorouracil Treatment in Huh-7 Cells

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p=0.05) and protein (3.2±0.3-fold vs. vehicle, p=0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo. CONCLUSION/SIGNIFICANCE: Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor

Justice in transport as justice in access: applying Walzer's 'Spheres of Justice' to the transport sector

Contains fulltext : 111686.pdf (publisher's version ) (Open Access)19 p

Integration of the biophysical and social sciences using an indicator approach: Addressing water problems at different scales

To be operationally sustainable, any system of environmental management needs to be based on a truly holistic assessment of all of the relevant factors influencing it. This is of course a daunting task, demanding as it does detailed and reliable data, not only from both the physical and social sciences, but also incorporating some representation of that part of knowledge which could be described as non-scientific. This could be said to include the uncertainties of market forces and political will, as well as traditional knowledge systems, and artistic representation. Recognising the limitations of our own knowledge system is important if we are to make progress in the achievement of sustainability. The development of less deterministic models is a step forward in that direction. This paper provides some discussion on the challenges associated with the integration of data from different disciplines, and the application of that data at different scales. Alternative approaches to the assessment of water resources for policy making are highlighted, and the validity of using such assessments at different scales is discussed. Using the Water Poverty Index as illustration, examples are provided of how an integrated assessment framework can be used to provide consistency and transparency in decision-making, and how this can, in practice, be applied at a variety of scales