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.
Highlights
Hepatocellular carcinoma (HCC) is among the most frequent malignant tumors and the second most lethal cancer worldwide with a rising incidence and limited therapeutic options [1, 2]
This observation was expanded to the whole integrin family by examination of the dataset from a previously performed genome wide expression profiling after Cellular Apoptosis Susceptibility (CAS) silencing in HLE cells [21]
We show that CAS is linked to integrin expression in HCC, to integrin β1, and is essential for tumor cell motility in HCC cell lines
Summary
Hepatocellular carcinoma (HCC) is among the most frequent malignant tumors and the second most lethal cancer worldwide with a rising incidence and limited therapeutic options [1, 2]. Nuclear transport receptors are an integral part of the transport system and belong predominantly to the karyopherin protein superfamily [5] These include importins, exportins, and transportins which shuttle cargos between the nucleus and cytoplasm by passage through the nuclear pore complex (NPC) [7,8,9]. Classical protein import involves the recognition of a nuclear localization signal (NLS) on a cargo protein by importin-α (imp-α) and subsequent association with importin-β1 to form a trimeric www.impactjournals.com/oncotarget complex [10]. This importin/cargo complex transverses the NPC, dissociates in a RanGTP dependent manner and releases its transport substrate into the nucleoplasm [7]. These data suggest diverse and contextspecific functions of CAS that are still incompletely understood
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