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Endoplasmic reticulum stress and hepatocellular carcinoma: a new paradigm in tumor growth regulation

Final Activity Report Summary - ER STRESS AND HCC (Endoplasmic reticulum stress and hepatocellular carcinoma: a new paradigm in tumor growth regulation)

The endoplasmic reticulum (ER) is the sub-cellular compartment where secretory proteins enter the secretory pathway. This compartment is specialised for their folding and assembly. In such a calcium-rich, oxidising environment, nascent protein chains can be modified by addition of N-linked oligosaccharides and formation of intra- and inter-disulfide bonds prior to be exported in other compartments such as the Golgi apparatus. Maintenance of ER homeostasis has been found to be altered in many diseases such as diabetes, mono-allelic genetic and neurodegenerative diseases or upon viral infections. Under those circumstances, the ER triggers a conserved 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). In the course of this project we have developed the tools to evaluate the activation of the UPR in HCC tissues, identified new molecular complexes potentially involved in the disease and also characterised a modulator of the UPR.