Objective
The endoplasmic reticulum (ER) is the sub-cellular compartment where secretory proteins enter the secretory pathway. This compartment is specialized for their folding and assembly. When maintenance of ER homeostasis is altered, this compartment triggers a specific signalling pathway, named the Unfolded Protein Response (UPR), which leads to translation attenuation as well as the activation of specific transcriptional programs. These mechanisms aim to facilitate cell recovery and to repair when possible, the damages causing the alterations of ER functions. Recently, a link between ER stress and tumour growth and development has been proposed, with in particular, the high expression levels of the ER stress target proteins ATF-6 and XBP-1 correlated with the development of hepatocellular carcinoma (HCC). Based on the available literature and our current knowledge, we hypothesized that the activation of the UPR may represent a determining factor in HCC development. To test this hypothesis, we will at first characterize ER stress signalling networks in human primary hepatocytes and in cell lines derived from human HCC. These data will be analysed to identify potential ER stress signalling intermediates specific for HCC.
The selected targets will be validated for their involvement in ER stress signalling using an over-expression or silencing approach in HCC derived cell lines. These targets will be validated in human tumour biopsies in conjunction with the assessment of the activation of ER stress signalling pathways. Integration of these data with the information available for each tumour will then allow for the establishment of specific tumour signatures. Finally, this approach will also lead to the validation in situ of the ER stress targets identified previously, thus identifying potential therapeutic targets. In our last specific aim, we will design in vitro assays to screen chemical libraries in order to identify inhibitors/modulators of the relevant targets.
Fields of science
Call for proposal
FP6-2004-MOBILITY-12
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