| PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. | |
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MedLine Citation:
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PMID: 17130832 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The cooperation of Ras - extracellular signal-regulated kinase/mitogen-activated protein kinase and transforming growth factor (TGF)-beta signaling provokes an epithelial to mesenchymal transition (EMT) of differentiated p19(ARF) null hepatocytes, which is accompanied by a shift in malignancy and gain of metastatic properties. Upon EMT, TGF-beta induces the secretion and autocrine regulation of platelet-derived growth factor (PDGF) by upregulation of PDGF-A and both PDGF receptors. Here, we demonstrate by loss-of-function analyses that PDGF provides adhesive and migratory properties in vitro as well as proliferative stimuli during tumor formation. PDGF signaling resulted in the activation of phosphatidylinositol-3 kinase, and furthermore associated with nuclear beta-catenin accumulation upon EMT. Hepatocytes expressing constitutively active beta-catenin or its negative regulator Axin were employed to study the impact of nuclear beta-catenin. Unexpectedly, active beta-catenin failed to accelerate proliferation during tumor formation, but in contrast, correlated with growth arrest. Nuclear localization of beta-catenin was accompanied by strong expression of the Cdk inhibitor p16(INK4A) and the concomitant induction of the beta-catenin target genes cyclin D1 and c-myc. In addition, active beta-catenin revealed protection of malignant hepatocytes against anoikis, which provides a prerequisite for the dissemination of carcinoma. From these data, we conclude that TGF-beta acts tumor progressive by induction of PDGF signaling and subsequent activation of beta-catenin, which endows a subpopulation of neoplastic hepatocytes with features of cancer stem cells.. |
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Authors:
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A N M Fischer; E Fuchs; M Mikula; H Huber; H Beug; W Mikulits |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-11-20 |
Journal Detail:
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Title: Oncogene Volume: 26 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2007 May |
Date Detail:
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Created Date: 2007-05-17 Completed Date: 2007-06-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3395-405 Citation Subset: IM |
Affiliation:
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Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anoikis Carcinoma, Hepatocellular / metabolism*, pathology* Cell Differentiation Cell Line, Tumor Cell Nucleus / metabolism* Cell Proliferation Disease Progression Epithelial Cells / metabolism Humans Platelet-Derived Growth Factor / metabolism* Signal Transduction* Transforming Growth Factor beta / metabolism* beta Catenin / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Platelet-Derived Growth Factor; 0/Transforming Growth Factor beta; 0/beta Catenin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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