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Int. J. Mol. Sci. 2017, 18(10), 2119;

Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells

Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
Institute for Clinical Chemistry, Medical Faculty Mannheim, University of Heidelberg, University Hospital Mannheim, 68167 Mannheim, Germany
Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg Mannheim, 68167 Mannheim, Germany
GenXPro GmbH, 60438 Frankfurt am Main, Germany
Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, 1090 Vienna, Austria
Author to whom correspondence should be addressed.
Received: 21 August 2017 / Revised: 15 September 2017 / Accepted: 15 September 2017 / Published: 10 October 2017
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the “real-time” detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell–cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient’s survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells. View Full-Text
Keywords: hepatocellular carcinoma; TGF-β; transendothelial migration; SILAC; proteomics; bioinformatics hepatocellular carcinoma; TGF-β; transendothelial migration; SILAC; proteomics; bioinformatics

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Koudelkova, P.; Costina, V.; Weber, G.; Dooley, S.; Findeisen, P.; Winter, P.; Agarwal, R.; Schlangen, K.; Mikulits, W. Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 2119.

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