Evert, Matthias and Frau, Maddalena and Tomasi, Maria Lauda and Latte, Gavinella and Simile, Maria Maddalena and Seddaiu, Maria Antonietta and Zimmermann, A. and Ladu, Sara and Staniscia, T. and Brozzetti, Stefania and Solinas, Maria Giuliana and Dombrowski, F. and Feo, Francesco and Pascale, Rosa Maria and Calvisi, Diego Francesco (2013) Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value. British Journal of Cancer, Vol. 109 , p. 2654-2664. ISSN 0007-0920. eISSN 1532-1827. Article.
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The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown.
DNA-dependent protein kinase catalytic subuni, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT–PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan–Meier curves and multivariate Cox model were used to study the impact on clinical outcome.
Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient’s survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis.
DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.
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