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    Keywords: CELLS ; HEPATOCELLULAR-CARCINOMA ; MECHANISM ; COPY-NUMBER ; IMPORTIN-ALPHA ; HUMAN HOMOLOG ; SUSCEPTIBILITY GENE ; protein expression ; TARGET GENES ; SEGREGATION GENE CSE1
    Abstract: Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-alpha1 (imp-alpha1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-alpha1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P〈0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp-alpha1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp-alpha1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. CONCLUSION: The CAS/imp-alpha1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-alpha1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 24799195
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