Cellular apoptosis susceptibility (CAS) is linked to integrin β1 and required for tumor cell migration and invasion in hepatocellular carcinoma (HCC)
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Juliane Winkler1, Stephanie Roessler1, Carsten Sticht2, Amanda L. DiGuilio3, Elisabeth Drucker1, Kerstin Holzer1, Eva Eiteneuer1, Esther Herpel1,4, Kai Breuhahn1, Norbert Gretz2, Peter Schirmacher1, Alessandro Ori5,6, Stephan Singer1,5
1Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
2Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
3Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA
4Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
5European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany
6Leibniz Institute on Aging - Fritz-Lipmann-Institute e.V. (FLI), Jena, Germany
Stephan Singer, e-mail: [email protected]
Keywords: HCC, CAS, integrin β1, migration, nuclear transport
Received: October 14, 2015 Accepted: February 23, 2016 Published: March 23, 2016
Importins and exportins represent an integral part of the nucleocytoplasmic transport machinery with fundamental importance for eukaryotic cell function. A variety of malignancies including hepatocellular carcinoma (HCC) show de-regulation of nuclear transport factors such as overexpression of the exportin Cellular Apoptosis Susceptibility (CAS). The functional implications of CAS in hepatocarcinogenesis remain, however, poorly understood. Here we integrated proteomics, transcriptomics and functional assays with patient data to further characterize the role of CAS in HCC. By analyzing ~ 1700 proteins using quantitative mass spectrometry in HCC cells we found that CAS depletion by RNAi leads to de-regulation of integrins, particularly down-regulation of integrin β1. Consistent with this finding, CAS knockdown resulted in substantially reduced migration and invasion of HCC cell lines as analyzed by 2D ‘scratch’ and invasion chamber assays, respectively. Supporting the potential in vivo relevance, high expression levels of CAS in HCC tissue samples were associated with macroangioinvasion and poorer patient outcome. Our data suggest a previously unanticipated link between CAS and integrin signaling which correlates with an aggressive HCC phenotype.
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