title: Cellular apoptosis susceptibility (CAS) is linked to integrin β1 and required for tumor cell migration and invasion in hepatocellular carcinoma (HCC).
abstract: 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.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roessler
authors.affiliation: Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: DiGuilio
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Drucker
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Holzer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Eiteneuer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.affiliation: Medical Research Centre, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany.|Leibniz Institute on Aging - Fritz-Lipmann-Institute e.V. (FLI), Jena, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ori
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D029563:Cellular Apoptosis Susceptibility Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology
chemical_list: D029563:Cellular Apoptosis Susceptibility Protein; D019012:Integrin beta1
keywords: CAS; HCC; integrin β1; migration; nuclear transport