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Project A6

Dissecting TGF-b signaling in hepatocarcinogenesis

Principal Investigators: Prof. Dr. Steven Dooley, Dr. Nadja Meindl-Beinker


Short Summary

During carcinogenesis TGF-β turns from a tumor suppressor into a tumor promoter. We found an overexpression of Smad7 in HCCs, which provides tumor cells with a mechanism to escape TGF-β-dependent growth control in hepatocarcinogenesis. We will test this hypothesis with HCC samples, mouse HCC models and HCC cell lines and delineate the mechanism(s) leading to Smad7 overexpression. Further, we will analyze the modulation of TGF-β signaling during onset and progression of HCC, taking into account infection with HBV-and HCV infections. Ultimately, we aim to identify drugable targets in TGF-ß signalling.

 

List of relevant publications

  1. Weng H, Liu Y, Chen JL, Huang T, Godoy P, Hu JH, Zhou C, Stickel F, Marx A, Bohle RM, Zimmer V, Lammert F, Müller S, Mertens PR, Singer MV, Seitz HK, Dooley S (2009) The etiology of liver damage imparts TGF-b1 or IL-13 as driving force of fibrogenesis. Hepatology in press.
  2. Godoy P, Hengstler RG, Ilkavets I, Mayer C, Bachmann A, Müller A, Tuschl G, Müller S, Dooley S (2009) Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid de-differentiation and TGF-b-induced apoptosis. Hepatology [Epub ahead of print].
  3. Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, Gebhardt R, Kanzler S, Geier A, Breitkopf K, Wenig H, Mertens PR (2008) Hepatocyte specific Smad7 expression attenuates TGF-b mediated fibrogenesis and protects against liver damage. Gastroenterology 135:642-59.
  4. Meindl-Beinker NM, Dooley S (2008) TGF-β and hepatocyte trans-differentiation in liver fibrogenesis. J Gastroenterol Hepatol 23:122-27.
  5. Hamzavi J, Ehnert S, Godoy P, Weng H, Mertens PR, Heuchel R, Dooley S (2008) Genomic disruption of the Smad7 gene enhances CCl4 dependent liver damage and fibrogenesis in mice. J Cell Mol Med 12:2130-44.
  6. Weng H, Mertens PR, Gressner AM, Dooley S (2007) IFN-g abrogates profibrogenic TGF-b signaling in the liver by targeting expression of inhibitory and receptor Smads. J Hepatol 46:295-303.
  7. Weng H, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, Kanzler S, Heuchel R, Ueberham U, Gebhardt R, Breitkopf K, Dooley S (2007) Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology 46:1257-70.
  8. Purps O, Lahme B, Gressner AM, Meindl-Beinker NM, Dooley S (2007) Loss of TGF-beta dependent growth control during HSC transdifferentiation. Biochem Biophys Res Commun 353:841-47.
  9. Dooley S, Said HM, Gressner AM, Floege J, En Nia AA, Mertens PR (2006) YB-1 is the crucial mediator of antifibrotic IFN-g effects. J Biol Chem 281:1784-95.
  10. Seyhan H, Hamzavi J, Wiercinska E, Gressner AM, Mertens PR, Kopp J, Horch RE, Breitkopf K, Dooley S (2006) Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling. J Cell Mol Med 10:922-32.
  11. Weng H, Wang BE, Jia JD, Wu WF, Xian JZ, Mertens PR, Cai WM, Dooley S (2005) Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clinical Gastroenterology and Hepatology 3:819-28.
  12. S Dooley, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, ten Dijke P, Gressner AM (2003) Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125:178-191.
  13. Dooley S, Streckert M, Delvoux B, Gressner AM (2001) Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts. Biochem  Biophys  Res  Commun 283:554-62.
  14. Dooley S, Delvoux B, Streckert M, Bonzel L, Stopa M, ten Dijke P, Gressner AM (2001) TGF-b signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts. TGF-b signal transduction during transdifferentiation of hepatic stellate cells. FEBS Letters 502:4-10.
  15. Stopa M, Benes V, Ansorge W, Gressner AM, Dooley S (2000) Genomic locus and promoter region of rat SMAD7, an important antagonist of TGF-b signaling. Mammalian Genome 169-76.
  16. Stopa M, Anhuf D, Terstegen L, Gatsios P, Gressner AM, Dooley S (2000) Participation of Smad2, Smad3 and Smad4 in TGF-b-induced activation of Smad7. The TGF-b response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation. J Biol Chem 275:29308-17.
  17. Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner AM (2000) Modulation of TGF-b response and signaling during transdifferention of rat hepatic stellate cells to myofibroblasts. Hepatology 31:1094-06.
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