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Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2007 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 19, no 4, p. 683-94Article in journal (Refereed) Published
Abstract [en]

The transforming growth factor-beta (TGF-beta) regulates hepatocyte growth, inhibiting proliferation and inducing apoptosis. Indeed, escaping from the TGF-beta suppressor actions might be a prerequisite for liver tumour progression. In this work we show that TGF-beta plays a dual role in regulating apoptosis in FaO rat hepatoma cells, since, in addition to its pro-apoptotic effect, TGF-beta also activates survival signals, such as AKT, the epidermal growth factor receptor (EGFR) being required for its activation. TGF-beta induces the expression of the EGFR ligands transforming growth factor-alpha (TGF-alpha) and heparin-binding EGF-like growth factor (HB-EGF) and induces intracellular re-localization of the EGFR. Cells that overcome the apoptotic effects of TGF-beta undergo morphological changes reminiscent of an epithelial-mesenchymal transition (EMT) process. In contrast, TGF-beta does not activate AKT in adult hepatocytes, which correlates with lack of EGFR transactivation and no response to EGFR inhibitors. Although TGF-beta induces TGF-alpha and HB-EGF in adult hepatocytes, these cells show very low expression of TACE/ADAM 17 (TNF-alpha converting enzyme), which is required for EGFR ligand proteolysis and activation. Furthermore, adult hepatocytes do not undergo EMT processes in response to TGF-beta, which might be due, at least in part, to the fact that F-actin re-organization induced by TGF-beta in FaO cells require the EGFR pathway. Finally, results indicate that EGFR transactivation does not block TGF-beta-induced cell cycle arrest in FaO cells, but must be interfering with the pro-apoptotic signalling. In conclusion, TGF-beta is a suppressor factor for adult quiescent hepatocytes, but not for hepatoma cells, where it plays a dual role, both suppressing and promoting carcinogenesis.

Place, publisher, year, edition, pages
2007. Vol. 19, no 4, p. 683-94
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Cell Biology
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URN: urn:nbn:se:uu:diva-339284DOI: 10.1016/j.cellsig.2006.09.002PubMedID: 17055226OAI: oai:DiVA.org:uu-339284DiVA, id: diva2:1175323
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-01-17

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