Bonjour à tous,
Le Dr. Cynthia Lebeaupin, post-doctorante dans le laboratoire du Dr. Randal J. Kaufman (Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037 USA), viendra nous présenter ses travaux :
The endoplasmic reticulum stress transducer ATF6 drives fatty liver disease progression to cancer
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a rising cause of cancer mortality. HCC related to metabolic overload is on the rise, with fatty liver disease rapidly becoming the dominant HCC etiology. We have shown that endoplasmic reticulum (ER) stress plays a crucial role in chronic liver disease progression. Under ER stress, hepatocytes activate the unfolded protein response (UPR), processing activating transcription factor 6 (ATF6p90) to a transcriptionally active nuclear-localized ATF6p50 fragment to enforce adaptive programs. While we previously demonstrated ATF6 is required to survive acute ER stress and resolve lipid accumulation in the liver, the role of ATF6 in chronic ER stress with fatty liver disease-related HCC has not been examined. Our recent findings show that ATF6 promotes HCC: a) Nuclear ATF6p50 is elevated in human HCC tumor samples compared to non-tumor tissues and associated with poor patient prognosis; b) Expression of ATF6p50 promotes HCC in mice; and c) Deletion of ATF6 reduces tumor incidence in carcinogen, dietary and transgenic mouse models. Hence, aberrant ATF6 activation promotes fatty liver disease progression to HCC, which is counter-intuitive from its adaptive role in acute ER stress in hepatocytes, thus opening entirely novel objectives for investigation.
Venez nombreux!
